Camrelizumab-induced oral lichenoid reaction with subepithelial CD4+ T-cell infiltration.

INTRODUCTION: Camrelizumab is a novel anti-programed cell death-1 (PD-1) antibody that has been investigated for the treatment of various malignancies. Increasing immune-related adverse events have been reported in clinical practice, with CD4+ T-cell-mediated-reactive cutaneous capillary endothelial proliferation being the most common. Camrelizumab-induced oral lichenoid reaction (OLR) appears to be a rare adverse effect compared with other anti-PD therapies induced OLR, with the main pathogenesis of activated CD8+ T cells mediating autoimmune reactions. Herein, we report a rare case of camrelizumab-induced OLR and a possible pathogenic mechanism of subepithelial CD4+ T-cell infiltration. CASE REPORT: A 57-year-old male patient, who was diagnosed with metastatic esophageal squamous cell carcinoma three years prior, presented with a two-month history of oral erosion that developed while under camrelizumab therapy. Diffuse erythematous and erosive lesions surrounded by bilateral white lesions on the buccal mucosa were detected in his physical examination. Hematoxylin and eosin staining of the lesions revealed the presence of basal keratinocyte degeneration and band-like subepithelial T-cell infiltration. The immunostaining for CD4 on T-cell was positive, while CD8 were sporadically positive. Flow cytometry showed a gradual increase in the CD4+ T-cell proportion in the peripheral blood, with the CD8+ T-cell percentage almost unchanged and in the normal range. We obtained a score of 6 based on the Naranjo algorithm, which means a probable adverse drug reaction. MANAGEMENT AND OUTCOME: The patient exhibited notable improvement after two weeks of treatment with topical glucocorticoid without regulating his immunotherapy, and remained in stable condition in the follow-up. DISCUSSION: This case may offer new insight to clinicians on the pathogenesis of anti-PD-1-induced OLR. More critically, it may provide some ideas for a more precise anti-PD therapy or corresponding combination therapy for patients becoming resistant to immunotherapy due to exhausted CD4+ T-cell responses in the tumor microenvironment.

Combination of downregulating FEN1 and PD-1 blockade enhances antitumor activity of CD8+ T cells against HNSCC cells in vitro.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) and human leukocyte antigen/major histocompatibility complex (HLA/MHC) are two main kinds of immunophenotypes affecting the susceptibility to anti-PD therapy. Our previous study found that down-regulation of flap endonuclease-1 (FEN1) could not only inhibit PD-L1 expression, but also upregulate HLA expression in head and neck squamous cell carcinoma (HNSCC). We aimed to clarify whether downregulating FEN1 cloud enhance the response to PD-1 blockade, and possible mechanisms in HNSCC in vitro. METHODS: Differential expression of FEN1 in HNSCC tumor and normal tissues were explored in the TIMER and TISIDB datasets. A HNSCC cells/CD8+ T cells co-culture model was established. HNSCC cell cycle and apoptosis were recorded by flow cytometry. Immune activity markers of granzyme A, granzyme B, and PRF1 expressed in the CD8+ T cells, and IFN-γ, IL-2, and TNF-α secreted in the supernatants were detected by western blot, ELISA, respectively. RESULTS: FEN1 was highly expressed in HNSCC and associated with low immune infiltration. Downregulating FEN1 could induce HLA class I expression, and inhibit PD-L1 expression in HNSCC cells. Functionally, FEN1 knockdown enhanced the response to αPD-1 mAb by mediating G2/M phase arrest, apoptosis of HNSCC cells. Mechanistically, targeting FEN1 synergized with αPD-1 mAb could reinforce the antitumor response of CD8+ T cells against HNSCC cells, as indicated by increasing granzyme A, granzyme B, and PRF1 expressions, and promoting IFN-γ, IL-2, and TNF-α secretions. CONCLUSION: These findings might offer a potential combined strategy for patients resistant to anti-PD therapy via combining FEN1 knockdown and PD-1 blockade.

Down-regulation of DNA key protein-FEN1 inhibits OSCC growth by affecting immunosuppressive phenotypes via IFN-γ/JAK/STAT-1.

Oral squamous cell carcinoma (OSCC) escape from the immune system is mediated through several immunosuppressive phenotypes that are critical to the initiation and progression of tumors. As a hallmark of cancer, DNA damage repair is closely related to changes in the immunophenotypes of tumor cells. Although flap endonuclease-1 (FEN1), a pivotal DNA-related enzyme is involved in DNA base excision repair to maintain the stability of the cell genome, the correlation between FEN1 and tumor immunity has been unexplored. In the current study, by analyzing the clinicopathological characteristics of FEN1, we demonstrated that FEN1 overexpressed and that an inhibitory immune microenvironment was established in OSCC. In addition, we found that downregulating FEN1 inhibited the growth of OSCC tumors. In vitro studies provided evidence that FEN1 knockdown inhibited the biological behaviors of OSCC and caused DNA damage. Performing multiplex immunohistochemistry (mIHC), we directly observed that the acquisition of critical immunosuppressive phenotypes was correlated with the expression of FEN1. More importantly, FEN1 directly or indirectly regulated two typical immunosuppressive phenotype-related proteins human leukocyte antigen (HLA-DR) and programmed death receptor ligand 1 (PD-L1), through the interferon-gamma (IFN-γ)/janus kinase (JAK)/signal transducer and activator transcription 1 (STAT1) pathway. Our study highlights a new perspective on FEN1 action for the first time, providing theoretical evidence that it may be a potential immunotherapy target for OSCC.

Glycolysis reprogramming in cancer-associated fibroblasts promotes the growth of oral cancer through the lncRNA H19/miR-675-5p/PFKFB3 signaling pathway.

As an important component of the tumor microenvironment, cancer-associated fibroblasts (CAFs) secrete energy metabolites to supply energy for tumor progression. Abnormal regulation of long noncoding RNAs (lncRNAs) is thought to contribute to glucose metabolism, but the role of lncRNAs in glycolysis in oral CAFs has not been systematically examined. In the present study, by using RNA sequencing and bioinformatics analysis, we analyzed the lncRNA/mRNA profiles of normal fibroblasts (NFs) derived from normal tissues and CAFs derived from patients with oral squamous cell carcinoma (OSCC). LncRNA H19 was identified as a key lncRNA in oral CAFs and was synchronously upregulated in both oral cancer cell lines and CAFs. Using small interfering RNA (siRNA) strategies, we determined that lncRNA H19 knockdown affected proliferation, migration, and glycolysis in oral CAFs. We found that knockdown of lncRNA H19 by siRNA suppressed the MAPK signaling pathway, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and miR-675-5p. Furthermore, the lncRNA H19/miR-675-5p/PFKFB3 axis was involved in promoting the glycolysis pathway in oral CAFs, as demonstrated by a luciferase reporter system assay and treatment with a miRNA-specific inhibitor. Our study presents a new way to understand glucose metabolism in oral CAFs, theoretically providing a novel biomarker for OSCC molecular diagnosis and a new target for antitumor therapy.

Tacrolimus 0.03% ointment treatment in exfoliative cheilitis: A randomised controlled clinical trial and monitoring blood concentration.

BACKGROUND: Tacrolimus has been used to treat various inflammatory skin diseases, but its safety for topical application on the oral mucosa is unknown. Exfoliative cheilitis (EC) is a chronic inflammatory disorder of the lips characterised by repeated scaling; it is difficult to manage. The aim of this study was to assess the efficacy and safety of tacrolimus 0.03% ointment as a topical treatment in patients with EC. METHODS: In this randomised controlled clinical trial, 40 patients with EC were randomly assigned to receive either tacrolimus 0.03% ointment (experimental group, n = 20) or triamcinolone acetonide 0.1% cream (control group, n = 20) treatment for a 3-week period. Medication was administered in 3, 2 and 1 daily doses during the first, second and third weeks, respectively. The patients with complete healing were followed up for 3 months. The clinical outcomes were measured, including the scores regarding signs (scale, dryness, rhagades and swelling) and symptoms (rough, dry, pain, pruritus and burning sensation) at every visit. Blood concentrations of tacrolimus were assessed. RESULTS: After the 3-week treatment, healing rates of scale in the experimental and control groups were 65% and 10%, respectively (P = .018). Improvement in all signs and two symptoms (rough, pruritus) was much greater in the experimental group (P < .05). The 3-month recurrence rate was higher in the control group (P = .029). Tacrolimus blood concentrations were in the safe range (< 5 ng/mL). CONCLUSION: Topical tacrolimus 0.03% ointment has good short-term efficacy and safety for treating EC.

A personalized computational model predicts cancer risk level of oral potentially malignant disorders and its web application for promotion of non-invasive screening.

BACKGROUND: Despite their high accuracy to recognize oral potentially malignant disorders (OPMDs) with cancer risk, non-invasive oral assays are poor in discerning whether the risk is high or low. However, it is critical to identify the risk levels, since high-risk patients need active intervention, while low-risk ones simply need to be follow-up. This study aimed at developing a personalized computational model to predict cancer risk level of OPMDs and explore its potential web application in OPMDs screening. METHODS: Each enrolled patient was subjected to the following procedure: personal information collection, non-invasive oral examination, oral tissue biopsy and histopathological analysis, treatment, and follow-up. Patients were randomly divided into a training set (N = 159) and a test set (N = 107). Random forest was used to establish classification models. A baseline model (model-B) and a personalized model (model-P) were created. The former used the non-invasive scores only, while the latter was incremented with appropriate personal features. RESULTS: We compared the respective performance of cancer risk level prediction by model-B, model-P, and clinical experts. Our data suggested that all three have a similar level of specificity around 90%. In contrast, the sensitivity of model-P is beyond 80% and superior to the other two. The improvement of sensitivity by model-P reduced the misclassification of high-risk patients as low-risk ones. We deployed model-P in web.opmd-risk.com, which can be freely and conveniently accessed. CONCLUSION: We have proposed a novel machine-learning model for precise and cost-effective OPMDs screening, which integrates clinical examinations, machine learning, and information technology.

Site preference and tetragonal distortion in palladium-rich Heusler alloys.

In this work, two kinds of competition between different Heusler structure types are considered, one is the competition between XA and L21 structures based on the cubic system of full-Heusler alloys, Pd2 YZ (Y = Co, Fe, Mn; Z = B, Al, Ga, In, Tl, Si, Ge, Sn, Pb, P, As, Sb). Most alloys prefer the L21 structure; that is, Pd atoms tend to occupy the a (0, 0, 0) and c (0.5, 0.5, 0.5) Wyckoff sites, the Y atom is generally located at site b (0.25, 0.25, 0.25), and the main group element Z has a preference for site d (0.75, 0.75, 0.75), meeting the well known site-preference rule. The difference between these two cubic structures in terms of their magnetic and electronic properties is illustrated further by their phonon dispersion and density-of-states curves. The second type of competition that was subjected to systematic study was the competitive mechanism between the L21 cubic system and its L10 tetragonal system. A series of potential tetragonal distortions in cubic full-Heusler alloys (Pd2 YZ) have been predicted in this work. The valley-and-peak structure at, or in the vicinity of, the Fermi level in both spin channels is mainly attributed to the tetragonal ground states according to the density-of-states analysis. ΔE M is defined as the difference between the most stable energy values of the cubic and tetragonal states; the larger the value, the easier the occurrence of tetragonal distortion, and the corresponding tetragonal structure is stable. Compared with the ΔE M values of classic Mn2-based tetragonal Heusler alloys, the ΔE M values of most Pd2CoZ alloys in this study indicate that they can overcome the energy barriers between cubic and tetragonal states, and possess possible tetragonal transformations. The uniform strain has also been taken into consideration to further investigate the tetragonal distortion of these alloys in detail. This work aims to provide guidance for researchers to further explore and study new magnetic functional tetragonal materials among the full-Heusler alloys.

Regulation of proliferation and cell cycle by protein regulator of cytokinesis 1 in oral squamous cell carcinoma.

Protein regulator of cytokinesis 1 (PRC1), a microtubule-associated protein, has emerged as a critical regulator of proliferation and apoptosis, acting predominantly in numerous tumors. However, its function in oral squamous cell carcinoma (OSCC) is still unknown. To establish the roles of PRC1 in OSCC, 95 oral clinical samples (54 OSCC, 24 oral leukoplakia [OLK], and 17 normal oral mucosa) and seven oral cell lines (6 OSCC and 1 normal oral cell lines) were analyzed using a series of molecular and genomic assays both in vivo and in vitro were conducted in this study. Herein, we provide evidence demonstrating that expression of PRC1 closely correlates with the degree of epithelial dysplasia in OLK (n = 24) (p < 0.001), and the poor differentiation, large tumor volume, lymph node metastasis, and high-clinical stage in OSCC (n = 54) (p < 0.05), illustrating that PRC1 has a promotive influence on tumor progression in OSCC. Simultaneously, we observed that PRC1 knockdown in OSCC cell lines caused G2/M phase arrest (p < 0.05), inhibited cell proliferation in vitro (p < 0.05) and tumor growth in vivo (p < 0.001). Furthermore, the effects of PRC1 on the regulation of proliferation and cell cycle transition in OSCC samples were mediated by p53. The p53/PRC1/EGFR signaling pathway was found to be implicated in the tumor progression of OSCC. Based on our data, we demonstrate that PRC1 is a key factor in regulating proliferation and the cell cycle, pointing to the potential benefits of PRC1-targeted therapies for OSCC.

FEN1 expression in oral carcinoma-associated fibroblasts and its relationship with PCNA / 口腔疾病防治

Objective@#To research the expression levels of FEN1 and PCNA in carcinoma-associated fibroblasts (CAFs) and analyze their correlation. @*Methods@#Fresh specimens of oral squamous cell carcinoma tissues and normal oral mucosal tissues excised during oral and maxillofacial plastic surgery were collected. Primary oral CAFs and normal fibroblasts (NFs) were obtained by tissue culture, identified by immunocytochemistry and divided into the CAF and NF groups. Western blot and quantitative real-time PCR were used to detect the protein and mRNA expression levels of both FEN1 and PCNA in the oral CAFs and NFs. The correlation between FEN1 and PCNA expression in oral CAFs was analyzed. @*Results@#Oral CAFs and oral NFs were successfully cultured and identified from 12 samples. Both the protein and mRNA expression levels of FEN1 and PCNA were higher in the oral CAFs than NFs, but there were no significant differences (P > 0.05). In the oral CAFs, the linear correlation coefficient between FEN1 and PCNA was 0.677 (P = 0.016) at the mRNA level, indicating a strong positive correlation; however, at the protein level, no correlation was found (P > 0.05). @*Conclusion@# In primary cultured oral CAFs and NFs, there were no significant differences in the FEN1 and PCNA protein and mRNA expression levels. However, in the CAFs, the mRNA levels of FEN1 and PCNA had a strong positive correlation. The relationship and the regulatory mechanism of the two genes require further study.

Synthesis and Biological Evaluation of a Series of Bile Acid Derivatives as FXR Agonists for Treatment of NASH.

Farnesoid X receptor (FXR) has become a particularly attractive target for the discovery of drugs for the treatment of liver and metabolic diseases. Obeticholic acid (INT-747), a FXR agonist, has advanced into clinical phase III trials in patients with nonalcoholic steatohepatitis (NASH), but adverse effects (e.g., pruritus, LDL increase) were observed. Pruritus might be induced by Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1), and there are chances to develop FXR agonists with higher selectivity over TGR5. In this letter, novel bile acids bearing different modifications on ring A and side chain of INT-747 are reported and discussed. Our results indicated that the side chain of INT-747 is amenable to a variety of chemical modifications with good FXR potency in vitro. Especially, compound 18 not only showed promising FXR potency and excellent pharmacokinetic properties, but also proved superior pharmacological efficacy in the HFD + CCl4 model.

Extramammary Paget's disease of the oral mucosa and perioral skin.

Extramammary Paget's disease (EMPD) is an unusual intraepidermal adenocarcinoma. Only 2 cases of EMPD in the oral mucosa have been reported previously. Here, we present the first report of a rare case of Paget's disease of the oral mucosa and perioral skin with extensive contiguous erythematous and erosive manifestations. Ultimately, the patient was treated with oral thalidomide for 8 weeks. We noticed an improvement with resolution of symptoms. A 3-year follow-up showed no relapse. Thus, this case may provide new insights to clinicians about treatment of EMPD. More importantly, we advise that dentists be vigilant about the possibility of some clinically significant conditions in patients with extensive nonspecific clinical lesions mimicking inflammatory or infectious diseases in the oral and maxillofacial regions, especially lesions that are refractory to long-term treatment. Requesting consultations with relevant clinical departments promptly and obtaining histopathologic confirmation at an early stage are crucial for early therapy and a better prognosis.

Composition-Driven Phase Boundary and Piezoelectricity in Potassium-Sodium Niobate-Based Ceramics.

The piezoelectricity of (K,Na)NbO3 ceramics strongly depends on the phase boundary types as well as the doped compositions. Here, we systematically studied the relationships between the compositions and phase boundary types in (K,Na) (Nb,Sb)O3-Bi0.5Na0.5AO3 (KNNS-BNA, A=Hf, Zr, Ti, Sn) ceramics; then their piezoelectricity can be readily modified. Their phase boundary types are determined by the doped elements. A rhombohedral-tetragonal (R-T) phase boundary can be driven in the compositions range of 0.035≤BNH≤0.040 and 0.035≤BNZ≤0.045; an orthorhombic-tetragonal (O-T) phase boundary is formed in the composition range of 0.005≤BNT≤0.02; and a pure O phase can be only observed regardless of BNS content (≤0.01). In addition, the phase boundary types strongly affect their corresponding piezoelectricities. A larger d33 (∼440-450 pC/N) and a higher d33* (∼742-834 pm/V) can be attained in KNNS-BNA (A=Zr and Hf) ceramics due to the involvement of R-T phase boundary, and unfortunately KNNS-BNA (A=Sn and Ti) ceramics possess a relatively poor piezoelectricity (d33≤200 and d33*<600 pm/V) due to the involvement of other phase structures (O-T or O). In addition, the underlying physical mechanisms for the relationships between piezoelectricity and phase boundary types were also discussed. We believe that comprehensive research can design more excellent ceramic systems concerning potassium-sodium niobate.

Tacrolimus 0.03% ointment in labial discoid lupus erythematosus: A randomized, controlled clinical trial.

In this randomized, controlled clinical trial to compare efficacy and safety, 41 patients with labial discoid lupus erythematosus (DLE) were randomized to 2 groups, either receiving tacrolimus 0.03% ointment (n = 22) or triamcinolone acetonide 0.1% cream (n = 19). Each patient was treated with 3, 2, and 1 daily doses in the first, second, and third weeks, respectively, for 1 course. After the 3 week treatment, patients with complete disappearance of erosion were followed up for 3 months. After the 3 week application, 20 participants in the tacrolimus group and 19 in the triamcinolone acetonide group completed the study. The rates of complete response were 70% and 89.5% in tacrolimus-treated and triamcinolone acetonide-treated patients, respectively, with no significant difference (P = .235). Reduction in erosion and erythema showed no significant difference between groups (P > .05). Final reduction in reticulation areas and numeric rating scale scores were significantly greater in the tacrolimus group than in the triamcinolone acetonide group (P = .013; P = .048, respectively). Only 1 patient receiving tacrolimus presented with slight discomfort. There was no significant difference in 3 month recurrence rate between the groups (P > .05). Topical tacrolimus is considered as effective as triamcinolone acetonide for the management of labial DLE.

Strong piezoelectricity in (1 - x)(K0.4Na0.6)(Nb0.96Sb0.04)O3-xBi0.5K0.5Zr1-ySnyO3 lead-free binary system: identification and role of multiphase coexistence.

Here we report a strong piezoelectric activity in (1 - x)(K0.4Na0.6)(Nb0.96Sb0.04)O3-xBi0.5K0.5Zr1-ySnyO3 lead-free ceramics by designing different phase boundaries. The phase boundaries concerning rhombohedral-orthorhombic-tetragonal (R-O-T) and rhombohedral-tetragonal (R-T) multiphase coexistence were attained by changing BKZS and Sn contents and then were identified by the X-ray diffraction patterns as well as temperature-dependent permittivity and ν1 Raman modes associated with BO6 perovskite octahedron. A high strain (strain = 0.21-0.28% and d33* = 707-880 pm/V) and a strong piezoelectric coefficient (d33 = 415-460 pC/N) were shown in the ceramics located at the multiphase coexistence region. The reported results of this work are superior to that (d33* ∼ 570 pm/V and d33 ∼ 416 pC/N) of the textured (K,Na,Li)(Nb,Ta,Sb)O3 ceramics [Nature 2004, 432, 84]. We believe that the material system of this work will become one of the most promising candidates for piezoelectric actuators.

(1 - x)(K0.48Na0.52)(Nb(0.95-y-z)Ta(z)Sb(y))O3-xBi0.5(Na0.82K0.18)0.5ZrO3 lead-free ceramics: composition dependence of the phase boundaries and electrical properties.

In this work, (1 - x)(K0.48Na0.52)(Nb(0.95-y-z)Ta(z)Sb(y))O3-xBi0.5(Na0.82K0.18)0.5ZrO3, {abbreviation: KNNST-BNKZ-x-y-z} lead-free piezoceramics were prepared by a conventional solid-state reaction method, and the composition dependence of their phase structures and electrical properties was systematically discussed. Doping with Sb(5+), Ta(5+), and BNKZ plays an important role on the phase boundaries as well as piezoelectric activity. A three-phase coexistence involving rhombohedral-orthorhombic-tetragonal (R-O-T) phases was observed in the ceramics with 0.0325 ≤ x ≤ 0.05, 0.035 ≤ x ≤ 0.065, 0.05 ≤ z ≤ 0.08, indicating that doping with BNKZ, Ta(5+), and Sb(5+) can induce the formation of such a phase boundary by simultaneously increasing TR-O and decreasing TO-T. Enhanced piezoelectric behavior was observed in the ceramics located in the composition region of the R-O-T phase boundary, and a high d33 value of 400 pC N(-1) can be attained by refining their compositions (e.g., x = 0.0325, y = 0.035, and z = 0.05), together with a high TC value of ∼240 °C. Of particular interest is that a large electric field-induced strain of 0.18% (Smax/Emax = 706 pm V(-1)) was also found in the ceramics with x = 0.0325, y = 0.035, and z = 0.05 under a low electric field of 2.5 kV mm(-1). As a result, the piezoelectric activity as well as the strain can be operated in the material system by refining x, y, and z content.

High strain in (K,Na)NbO3-based lead-free piezoceramics.

A high strain is important for practical applications of piezoelectric actuators. Here we reported a high strain in the (K,Na)NbO3 -based ceramics by doping alkaline earths or transition metals. The ceramics possess a high strain (∼0.29%) as well as a large converse piezoelectric coefficient (d33*) up to 688 pm/V, which almost matches that of PZT4 ceramics. The obtained d33* is high for nontextured (K,Na)NbO3-based ceramics. In addition, a higher d33 value (340-407 pC/N) was also attained in the ceramics. Enhanced d33 and d33* values of this work should be attributed to the multiphase coexistence's effect induced by alkaline earths or transition metals. We believe that our research can benefit the developments of (K,Na)NbO3 ceramics and widen their applications range.

New potassium-sodium niobate material system: a giant-d33 and high-T(C) lead-free piezoelectric.

In this work, we elucidate the influence of Bi(0.5)Li(0.5)ZrO3 (BLZ) content on the phase structure, microstructure, and electrical properties of (1 -x)K(0.40)Na(0.60)Nb(0.965)Sb(0.035)O3-xBi(0.5)Li(0.5)ZrO3 lead-free ceramics. We simultaneously achieved a giant d33 and a high T(C) in this material system. The coexistence of rhombohedral and tetragonal phases is responsible for such a large d33 in the ceramics with BLZ contents (x) ranging from 0.025 to 0.035. Doping with BLZ not only induces the formation of the phase boundary, but also maintains a high T(C). The ceramic with x = 0.03 shows an enhanced piezoelectric behaviour (d33 ~ 400 pC N(-1) and k(p) ~ 0.47) together with a high T(C) of 292 °C. A good temperature stability for ferroelectricity and piezoelectricity is also observed in these ceramics. This study is the first time that such a good comprehensive performance has been obtained in potassium-sodium niobate materials. We believe that this type of material system possessing giant-d33 and high-T(C) is a promising candidate for use in high-temperature piezoelectric devices.