Inhibition of RhoGEF/RhoA alleviates regorafenib resistance and cancer stemness via Hippo signaling pathway in hepatocellular carcinoma.

Patients with hepatocellular carcinoma (HCC) are vulnerable to drug resistance. Although drug resistance has been taken much attention to HCC therapy, little is known of regorafenib and regorafenib resistance (RR). This study aimed to determine the drug resistance pattern and the role of RhoA in RR. Two regorafenib-resistant cell lines were constructed based on Huh7 and Hep3B cell lines. In vitro and in vivo assays were conducted to study RhoA expression, the activity of Hippo signaling pathway and cancer stem cell (CSC) traits. The data showed that RhoA was highly expressed, Hippo signaling was hypoactivated and CSC traits were more prominent in RR cells. Inhibiting RhoA could reverse RR, and the alliance of RhoA inhibition and regorafenib synergistically attenuated CSC phenotype. Furthermore, inhibiting LARG/RhoA increased Kibra/NF2 complex formation, prevented YAP from shuttling into the nucleus and repressed CD44 mRNA expression. Clinically, the high expression of RhoA correlated with poor prognosis. LARG, RhoA, YAP1 and CD44 show positive correlation with each other. Thus, inhibition of RhoGEF/RhoA has the potential to reverse RR and repress CSC phenotype in HCC.

Early administration of dobutamine in the treatment of septic shock patients with tumor-a retrospective comparative cohort study.

Background: Studies have found that dobutamine may be beneficial to protect organs function in patients with septic shock, but there is still a lack of relevant research in septic shock patients with tumor. The study sought to explore the role of the early administration of dobutamine in the treatment of septic shock patients with tumors. Methods: We retrospectively collected the data of tumor patients who developed septic shock at Sun Yat-sen University Cancer Center between June 2008 and November 2021. All the patients were divided into the following 3 groups: (I) the early administration group (<3 days, n=15); (II) the late administration group (≥3 days, n=22); and (III) the non-administration group (n=85). The primary observation indicator was 28-day mortality, and the secondary observation indicators included the shock reversal rate, the length of stay in the intensive care unit (ICU) and the duration of mechanical ventilation. There was no statistical difference in the basic data of the three groups. Results: The early administration group had a significant decrease in 28-day mortality compared to the late and non-administration groups (log-rank P=0.018). The comparison between the groups showed that the 28-day mortality of the early administration group was significantly lower than that of the non-administration group [20.0% vs. 58.8%, P=0.013, hazard ratios (HRs) =0.248, 95% confidence intervals (CIs): 0.077-0.796]. There was no statistically significant difference in 28-day mortality between the late administration group and the non-administration group (63.6% vs. 58.8%, P=0.682, HR =0.983, 95% CI: 0.543-1.778). Additionally, the early administration group had a significantly increased shock reversal rate (P=0.014), shortened length of stay in the ICU (P<0.001), and reduced duration of mechanical ventilation (P=0.049). Conclusions: Early use of dobutamine may be beneficial to reduce the in-hospital mortality of septic shock patients with tumor, but the sample size of this study was small, which still needs to be confirmed by a multi-center randomized controlled clinical study.

Garnet secondary ion mass spectrometry oxygen isotopes reveal crucial roles of pulsed magmatic fluid and its mixing with meteoric water in lode gold genesis.

SignificanceThere is a common consensus that lode gold deposits mostly precipitated from metamorphic fluids via fluid boiling and/or fluid-rock interaction, but whether magmatic hydrothermal fluids and the mixing of such fluids with an external component have played a vital role in the formation of lode gold deposits remains elusive. We use garnet secondary ion mass spectrometry oxygen isotope analysis to demonstrate that the world-class Dongping lode gold deposit has been formed by multiple pulses of magmatic hydrothermal fluids and their mixing with large volumes of meteoric water. This study opens an opportunity to tightly constrain the origin of lode gold deposits worldwide and other hydrothermal systems that may have generated giant ore deposits in the Earth's crust.

Clinical study of periodontal endoscope-assisted subgingival scaling in the treatment of residual pocket.

OBJECTIVES: To compare the treatment effects of periodontal endoscope-assisted and traditional subgingival scaling on residual pockets. METHODS: A total of 13 patients with periodontitis from Dept. of Periodontics, West China Hospital of Stomatology, Sichuan University were recruited. After 4-6 weeks of initial treatment, the residual pockets with a probing depth (PD) of ≥4 mm and attachment loss (AL) of ≥4 mm and bleeding on probing were examined with traditional (control group) and periodontal endoscope-assisted subgingival scaling (endoscopy group) in a randomly controlled split-mouth design. At baseline and 6 weeks and 3 months after treatment, plaque index (PLI), PD, AL, and bleeding index (BI) were measured. Differences in these clinical parameters within and between groups and patient-reported outcomes were compared. RESULTS: A total of the 694 sites of 251 teeth were included in this trial. Both groups showed significant improvement in each periodontal parameters 6 weeks and 3 months after treatment (P<0.001). For sites in a single-rooted tooth, sites with PD≥5 mm, and sites without vertical alveolar bone resorption and furcation involvement, the PD in endoscopy group was significantly lower than that in the control group at 6 weeks and 3 months after treatment (P<0.05). CONCLUSIONS: Periodontal endoscope-assisted subgingival scaling resulted in better effects than traditional subgingival scaling when the residual pockets were in a single-rooted tooth, with a PD of ≥5 mm but without vertical alveolar bone resorption and furcation involvement.

Research progress on two-component signal transduction systems in Porphyromonas gingivalis.

Porphyromonas gingivalis (P. gingivalis), a Gram-negative oral anaerobe, is considered to be a major pathogenic agent involved in the onset and progression of chronic periodontitis. P. gingivalis must be able to perceive and respond to the complicated changes in host to survive the environmental challenges, in which the two-component signal transduction systems (TCSs) play critical roles by connecting input signals to cellular physiological output. Canonical TCS consists of a sensor histidine kinase and a cognate response regulator that functions via a phosphorylation cascade. In this review, the roles of TCSs in P. gingivalis were demonstrated by illustrating the target genes and modulation modes, which may help elucidate the underlying mechanisms in future studies.

[Treatment strategy for pregnancy epulis].

Pregnancy epulis is a tumor-like lesion with high prevalence in China. The local lesion, the general condition of the pregnant patient, and the complications during treatment should be taken into consideration when making a treatment plan for pregnancy epulis. In this study, three representative pregnancy epulis cases were presented, and related studies at home and aboard were reviewed to summarize the etiology, differential diagnosis, treatment, and prevention of pregnancy epulis and share the clinical experience in the treatment of pregnancy epulis.

[Role of bone morphogenetic protein 1/tolloid proteinase family in the development of teeth and bone].

The bone morphogenetic protein (BMP) 1/tolloid (TLD) proteinase family is a group of important metalloproteinases, which play key roles in the growth and development of tissues and organs via regulating the biosynthetic processing of the extracellular matrix. Clinical reports have revealed that mutations in the genes encoding BMP1/TLD proteinases lead to dentinogenesis imperfecta type Ⅰ, accompanied with osteogenesis imperfecta. Therefore, this proteinase family is essential for the development of hard tissues. In this study, we review the research progress in the function and mechanism of the BMP1/TLD proteinase family in the development of teeth and bone.

[Research progress on substitutes for autogenous soft tissue grafts in mucogingival surgery].

Mucogingival surgery is a general term for periodontal surgeries that correct aberrant periodontal soft tissues. Conventional mucogingival surgeries with pedicle flap or autologous soft tissue graft for treatment of gingival recession and insufficient keratinized tissues are always related to disadvantages such as need for a second surgery site, limited supplies, and complaints for postoperative discomfort. In this regard, research and application of soft tissue substitutes have gained increasing attention. Various kinds of soft tissue substitutes, including acellular dermal matrix and xenogeneic collagen matrix, have been developed and applied to clinical treatment. This review aims to summarize advances in research of the characteristics and clinical effectiveness of several soft tissue substitutes and provide references for clinical application.

[Expression of triggering receptors expressed by myeloid cells-1 in macrophages stimulated by Porphyromonas gingivalis-lipopolysaccharide].

OBJECTIVE: Soluble triggering receptors expressed by myeloid cells-1 (sTREM-1) and inflammatory cytokine tumor necrosis factor-α (TNF-α) in macrophage cells were stimulated by Porphyromonas gingivalis-lipopolysaccharide (Pg-LPS) to investigate the expression of triggering receptors expressed by myeloid cells-1 (TREM-1) and further explore the correlation between TREM-1 and the pathogenesis of periodontitis. METHODS: THP-1 cells (a human monocytic cell line derived from an acute monocytic leukemia patient) were induced to differentiate THP-1 macrophages by phorbol-12-myristate-13-acetate and were injected with 0 (blank control), 0.5, or 1.0 µg·mL⁻¹ Pg-LPS. The THP-1 cells were then grouped in accordance with incubation time, and each group was incubated for 4, 6, 12, or 24 h. The expression of the TREM-1 mRNA in macrophages was detected by real-time quantitative polymerase chain reaction, while the expression of TREM-1 protein was detected by Western blot; the site where TREM-1 protein expression was observed in macrophages was detected by immunofluorescence staining, and the expression of soluble sTREM-1 and TNF-α in cell culture medium was detected by enzyme-linked immunosorbent assay. RESULTS: Compared with the blank control group, the expression of TREM-1 mRNA, TREM-1 protein, and sTREM-1 in Pg-LPS-stimulated macrophages was significantly upregulated (P<0.05). The expression of TREM-1 mRNA, TREM-1 protein, and sTREM-1 in the supernatant of cell culture was higher in the 1.0 µg·mL⁻¹ Pg-LPS group than in the 0.5 µg·mL⁻¹ group; this expression was statistically significant since the 6, 4, and 4 h time point (P<0.05). Cell immunofluorescence staining showed that TREM-1 protein was positive when the THP-1 macrophages was stimulated by Pg-LPS (1.0 µg·mL⁻¹) for 24 h, and the staining sites of TREM-1 were mainly located in the cell membrane of the macrophages (P<0.05). The expression level of TNF-α increased in groups stimulated by Pg-LPS, and the expression level of TNF-α was significantly higher in 1.0 µg·mL⁻¹ Pg-LPS stimulated groups than in 0.5 µg·mL⁻¹ Pg-LPS-stimulated groups since the 6 h time point (P<0.05). The expressions of TREM-1 mRNA, TREM-1 protein, and sTREM-1 in 0.5 µg·mL⁻¹ Pg-LPS-stimulated macrophages were positively correlated with one another (r=1, P<0.05), but no statistically significant correlation was found in the expression of TNF-α. The positive correlation between sTREM-1 and TNF-α expressions was detected when macrophages were stimulated by 1.0 µg·mL⁻¹ Pg-LPS (r=1, P<0.05). CONCLUSIONS: The expression of TREM-1 mRNA, TREM-1 protein, and sTREM-1 in the culture supernatant in Pg-LPS-stimulated macrophages was significantly upregulated on the basis of the concentration of Pg-LPS; moreover, their upregulation was positively correlated with one another. The expression of TNF-α in the supernatant of cell culture was also upregulated and was positively correlated with the expression of sTREM-1 at the group of high Pg-LPS concentration (1.0 µg·mL⁻¹). Results reveal that TREM-1, which has been realized as a proinflammatory receptor protein, can promote the development of periodontitis by regulating the expression of TNF-α in macrophages.

Sonography for diagnosis of benign and malignant tumors of the nose and paranasal sinuses.

OBJECTIVES: The purpose of this study was to demonstrate the reliability of sonography for diagnosis of nose and paranasal sinus tumors. METHODS: Ninety-six consecutive patients with tumors underwent sonography and computed tomography (CT) before surgical treatment. Tumor detectability and imaging findings were evaluated independently and then compared with pathologic findings. RESULTS: Of 96 tumors, 75 were detected by sonography, for a detectability rate of 78.1%; 93 tumors were detected by CT, for a detectability rate of 96.9%. By comparison, sonography showed a trend toward higher detectability of nasal vestibular tumors than CT (87.5% for sonography versus 50.0% for CT) and small lumps on the wing of the nose (78.8% for sonography versus 33.3% for CT). Among the sonographic features, boundary, shape, internal echo, calcification, bone invasion, vascular pattern, and cervical lymph node metastasis all had significantly positive correlations with malignancy (P < .05), but size did not (P = .324). In addition, the vascular resistive index for malignant tumors was significantly higher (mean ± SD, 0.66 ± 0.20) than the index for benign lesions (0.24 ± 0.30; P < .001). Moreover, the detection rate for grade 1-3 (small-large) blood flow in benign lesions was only 43.8%, whereas the rate for malignant tumors was 97.7% (P < .001). CONCLUSIONS: The vascular pattern may be a promising predictive indicator for distinguishing benign and malignant tumors of the nose and paranasal sinuses. Consequently, sonography has high value for diagnosis of benign and malignant tumors of the nose and paranasal sinuses, especially for nasal vestibular tumors and small lumps on the wing of the nose.