A multi-center, single-arm, phase II study of anlotinib plus paclitaxel and cisplatin as the first-line therapy of recurrent/advanced esophageal squamous cell carcinoma.

BACKGROUND: Anlotinib, a tyrosine kinase inhibitor, has shown encouraging anti-tumor activity in esophageal squamous cell carcinoma (ESCC). This study was designed to assess the efficacy and safety of anlotinib plus paclitaxel and cisplatin (TP) as first-line therapy for advanced ESCC. METHODS: In a multi-center, single-arm, phase II clinical trial, patients (aged > 18 years) with ESCC, which was judged to be locally advanced, recurrent, or metastatic, received 10 mg oral anlotinib once daily on days 1-14, 135 mg/m2 intravenous paclitaxel on day 1, and 60-75 mg/m2 intravenous cisplatin on days 1-3 every 3 weeks for a maximum of 4-6 cycles as the initial therapy in five centers in China. Subsequently, patients received anlotinib monotherapy (10 mg) as maintenance therapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-seven patients were enrolled in this study between October 2019 and March 2021. The median follow-up was 14.04 months (IQR, 9.30-19.38). Of 46 with assessable efficacy, the median PFS and median overall survival were 8.38 months (95% CI, 6.59-10.17) and 18.53 months (95% CI, 13.11-23.95), respectively. The objective response rate was 76.1% (95% CI, 61.2-87.4%), with 4 (8.7%) complete responses and 31 (67.4%) partial responses. The disease control rate was 91.3% (95% CI, 79.2-97.6%). The median duration of response was 6.80 months (95% CI, 4.52-9.08), and 1 patient had an ongoing response for 23 months. Subgroup analysis revealed no association between clinical factors and survival or response. Of the 47 patients with assessable safety, the main grade ≥ 3 treatment-emergent adverse events (TEAEs) were neutropenia (17.0%), bone marrow suppression (12.8%), and vomiting (10.6%). No treatment-related deaths or serious TEAEs were observed. Notably, higher c-Kit levels were an independent factor for superior PFS (HR = 0.032; 95% CI, 0.002-0.606; P = 0.022). CONCLUSIONS: The study demonstrated a manageable safety profile and durable clinical response of anlotinib plus TP as first-line therapy in advanced ESCC, which suggested a potential therapeutic option for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04063683. Registered 21 August 2019.

Copper-Catalyzed Asymmetric Ring-Opening Reaction of Cyclic Diaryliodonium Salts with Imides.

An efficient copper-catalyzed asymmetric ring-opening reaction of diaryliodonium salts with imides has been developed, affording a wide range of axially chiral 2-imidobiaryl compounds with excellent enantioselectivities and better convertibility. The potential utility of the current method has been supported by the synthesis of two known chiral ligands with better efficiency, which would be of great significance to the development of other catalytic asymmetric reactions.

Recent development and applications of semipinacol rearrangement reactions.

As has been well-recognized, semipinacol rearrangement functions as an exceptionally useful methodology in the synthesis of ß-functionalized ketones, creation of quaternary carbon centers, and construction of challenging carbocycles. Due to their versatile utilities in organic synthesis, development of novel rearrangement reactions has been a vibrant topic that continues to shape the research field. Recent breakthroughs in novel electrophiles, tandem processes, and enantioselective catalytic transformations further enrich the toolbox of this chemistry and spur the strategic applications of this methodology in natural product synthesis. These achievements will be discussed in this minireview.

The Effect of Porphyromonas gingivalis Lipopolysaccharide on the Pyroptosis of Gingival Fibroblasts.

Periodontitis is a chronic inflammatory disease induced by Porphyromonas gingivalis (P. gingivalis) and other pathogens. P. gingivalis release various virulence factors including lipopolysaccharide (LPS). However, whether P. gingivalis-LPS inducing pyroptosis in human gingival fibroblasts (HGFs) remains unknown. In present study, P. gingivalis-LPS decreased the membrane integrity of HGFs, and pyroptosis-associated cytokines were upregulated at the mRNA level. In addition, pyroptosis proteins were highly expressed in gingival tissues of periodontitis. P. gingivalis-LPS induced gingivitis in the rat model, and the expression level of pyroptosis-associated proteins increased. Together, P. gingivalis-LPS can activate the pyroptosis reaction, which may be a pro-pyroptosis status in a relative low concentration.

Effects of D-arginine on Porphyromonas gingivalis biofilm.

Porphyromonas gingivalis (P. gingivalis) is one of the major pathogenic bacteria of periodontitis or peri-implantitis. P. gingivalis tends to attach to the implant's neck with the formation of biofilm, leading to peri-implantitis. d-arginine has been shown to have a potential antimicrobial role. In this study, P. gingivalis was cultured in Brain Heart Infusion broth together with d-arginine. After 3 days (inhibition) or 6 days (dissociation), these were characterized using crystal violet (CV) staining for the biofilm, extracellular polysaccharide (EPS) production from the biofilm, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay for biofilm activation. Furthermore, the P. gingivalis biofilm was observed by scanning electron microscopy (SEM). d-arginine effectively reduced biomass accumulation and promoted dissociation at concentrations of ≥50 mM and 100 mM, respectively. Through CV staining, d-arginine concentrations of EPS production from the biofilm for inhibition and dissociation effects was ≥50 mM and 100 mM, respectively. In addition, d-arginine affected biofilm activation for the corresponding concentrations: ≥60 mM for inhibition and ≥90 mM for dispersal. Under SEM observation, d-arginine changed the P. gingivalis biofilm structure in relatively high concentrations for inhibition or dissociation, respectively. The authors concluded that d-arginine could inhibit the formation of P. gingivalis biofilm and promote the dissociation of P. gingivalis biofilm.

Water-soluble fluorescent unimolecular micelles: ultra-small size, tunable fluorescence emission from the visible to NIR region and enhanced biocompatibility for in vitro and in vivo bioimaging.

Fluorescent unimolecular micelles (FUMs) with multicolor emission acting as fluorescent nanoagents for optical fluorescence imaging have, for the first time, been reported. The FUMs show good water-solubility, ultra-small size, and enhanced biocompatibility, which endow the FUMs with versatile applications including organelle labeling, multicolor markers and high tumor accumulation, revealing that our design can serve as a rational strategy for the development of UM-based fluorescent nanoagents for bioprocess monitoring.

Early Changes in Apparent Diffusion Coefficient for Salivary Glands during Radiotherapy for Nasopharyngeal Carcinoma Associated with Xerostomia.

Objective: To evaluate the early changes in the apparent diffusion coefficient (ADC) of the salivary glands during radiotherapy (RT) and their association with the degree of xerostomia at 6 months after RT in patients with nasopharyngeal carcinoma (NPC). Materials and Methods: We enrolled 26 patients with NPC who underwent RT. Each patient underwent diffusion-weighted MRI of the salivary glands at rest and with gustatory stimulation within 1 week before RT and 2 weeks after the beginning of RT. The ADC at rest (ADCR) and increase and increase rate with stimulation (ADCI, ADCIR) of the submandibular and parotid glands were calculated. The differences in the variables' values between 2 weeks after the beginning of RT and baseline (ΔADCR, ΔADCI, and ΔADCIR) were compared to the degree of xerostomia at 6 months after RT. Results: The ADCR of the submandibular and parotid glands were both significantly higher at 2 weeks after the beginning of RT than found at baseline (both p < 0.01). The ADCI and ADCIR for the parotid glands were both significantly lower at 2 weeks after the beginning of RT than found at baseline (both p < 0.01). ΔADCI and ΔADCIR of the parotid glands were associated with the degree of xerostomia at 6 months after RT (r = -0.61 and -0.72, both p < 0.01). Conclusion: The ADCs of the salivary glands change early during RT. The differences in the ADC increase and increase rate of the parotid glands between 2 weeks after the beginning of RT and baseline were associated with the degree of xerostomia at 6 months after RT.

Celastrol suppresses the proliferation of lung adenocarcinoma cells by regulating microRNA-24 and microRNA-181b.

Cumulative evidence has indicated that celastrol may suppress cancer growth; however, the underlying mechanism requires further investigation. In the present study, A549 cells were treated with various concentrations of celastrol. Lung cancer cell proliferation was evaluated using an MTT assay and observed under a microscope. Cell apoptosis was detected by Annexin V fluorescein isothiocyanate/propidium iodide double-labeled flow cytometry. The results demonstrated that celastrol suppressed proliferation and induced apoptosis in a dose-independent manner. Celastrol may also decrease the phosphorylation levels of signal transducer and activator of transcription 3 (STAT3) and the B cell lymphoma-2 (Bcl-2)/Bcl-2 associated C protein (Bax) ratio. As microRNA (miR-24 and miR-181b) were predicated to target STAT3, STAT3 activation was inhibited in miR-24-or miR-181b-treated A549 cells compared with the control treatment. The ratio of Bcl-2/Bax was further reduced in miR-24 or miR-181b-treated A549 cells. The results were further confirmed by detecting in another lung adenocarcinoma cell line, LTEP-a-2. In summary, the results of the present study demonstrated that celastrol treatment suppressed the proliferation and induced apoptosis by regulating the expression levels of miR-24 and miR-181b.

MiR-320a effectively suppresses lung adenocarcinoma cell proliferation and metastasis by regulating STAT3 signals.

MicroRNAs play important roles in tumorigenesis of various types of cancers. MiR-320a can inhibits cell proliferation of some cancers, but the biologic roles of miR-320a in lung cancer need to be further studied. Here, we investigated the roles of miR-320a in suppressing the proliferation of lung adenocarcinoma cells. MiR-320a treatment was found to effectively suppress LTEP-a-2 and A549 cell proliferation, and induce more apoptotic cells with irradiation treatment compared with control treatment. Our results also showed that miR-320a, as a novel miRNA, directly regulated signal transducer and activator of transcription 3 (STAT3) and its signals, such as Bcl-2, Bax, and Caspase 3. The siRNA-inhibited STAT3 levels further proved its roles in regulating STAT3 signals. Moreover, miR-320a treatment effectively suppressed cancer cell growth in mice xenografts compared with controls, and significantly inhibited cell migration in vitro and in vivo. Our findings collectively demonstrated that miR-320a, by directly regulating STAT3 signals, not only suppressed cell proliferation and metastasis, but also enhanced irradiation-induced apoptosis of adenocarcinomia cells.

Invasive atypical thymic carcinoid: three case reports and literature review.

Atypical thymic carcinoid is an extremely rare thymic neuroendocrine tumor derived from the neuroendocrine system. The aims of this paper were to investigate the clinical features of atypical thymic carcinoid and collate information and experience to improve the diagnosis and treatment of this disease. We describe three cases of atypical carcinoid of the thymus; clinical features, pathological data, treatment modalities, and short-term patient outcomes were summarized and analyzed. The initial clinical symptoms and signs of all three patients were nonspecific and an anterior mediastinal mass was found in each patient on chest computed tomography scan. All three patients underwent surgical resection (total thymectomy and complete excision of the tumor), followed by postoperative radiotherapy, with or without chemotherapy. The diagnoses of three patients were confirmed by pathological and immunohistochemical evaluation. We also present a review of the literature to collate as much information as possible and provide a reference for proper diagnosis and treatment of atypical thyroid carcinoid.

Carbene-catalysed reductive coupling of nitrobenzyl bromides and activated ketones or imines via single-electron-transfer process.

Benzyl bromides and related molecules are among the most common substrates in organic synthesis. They are typically used as electrophiles in nucleophilic substitution reactions. These molecules can also be activated via single-electron-transfer (SET) process for radical reactions. Representative recent progress includes α-carbon benzylation of ketones and aldehydes via photoredox catalysis. Here we disclose the generation of (nitro)benzyl radicals via N-heterocyclic carbene (NHC) catalysis under reductive conditions. The radical intermediates generated via NHC catalysis undergo formal 1,2-addition with ketones to eventually afford tertiary alcohol products. The overall process constitutes a formal polarity-inversion of benzyl bromide, allowing a direct coupling of two initially electrophilic carbons. Our study provides a new carbene-catalysed reaction mode that should enable unconventional transformation of (nitro)benzyl bromides under mild organocatalytic conditions.

Comparison of long-term survival between temozolomide-based chemoradiotherapy and radiotherapy alone for patients with low-grade gliomas after surgical resection.

PURPOSE: This study was designed to compare the survival outcomes of temozolomide-based chemoradiotherapy (TMZ + RT) vs radiotherapy alone (RT-alone) for low-grade gliomas (LGGs) after surgical resection. PATIENTS AND METHODS: In this retrospective analysis, we reviewed postoperative records of 69 patients with LGGs treated with TMZ + RT (n=31) and RT-alone (n=38) at the Shandong Cancer Hospital Affiliated to Shandong University between June 2011 and December 2013. Patients in the TMZ + RT group were administered 50-100 mg oral TMZ every day until the radiotherapy regimen was completed. RESULTS: The median follow-up since surgery was 33 months and showed no significant intergroup differences (P=0.06). There were statistically significant intergroup differences in the progression-free survival rate (P=0.037), with 83.9% for TMZ-RT group and 60.5% for RT-alone group. The overall 2-year overall survival (OS) rate was 89.86%. Age distribution (≥45 years and <45 years) and resection margin (complete resection or not) were significantly associated with OS (P=0.03 and P=0.004, respectively). CONCLUSION: Although no differences were found in the 2-year OS between the TMZ + RT and RT-alone groups, there was a trend toward increased 2-year progression-free survival in the TMZ + RT group. With better tolerability, concurrent TMZ chemoradiotherapy may be beneficial for postoperative patients with LGGs. Age distribution and surgical margin are likely potential indicators of disease prognosis. The possible differences in long-term survival between the two groups and the links between prognostic factors and long-term survival may be worthy of further investigation.

Carbene-catalyzed desymmetrization of 1,3-diols: access to optically enriched tertiary alkyl chlorides.

The introduction of a chlorine atom to a carbon center in an enantioselective manner via conventional C-Cl bond formation is difficult. Here we report a new approach to this class of tertiary alkyl chlorides with high optical purities. Instead of forming a new C-Cl bond, our approach involves carbene-catalyzed desymmetrization of 2-chloro-1,3-diols as the key step to set up the chiral carbon center with excellent enantiomeric excess.

Meta-analysis of the association between selenium and gastric cancer risk.

To clarify the effects of selenium level on the risk of gastric cancer (GC) and GC mortality, a meta-analysis was performed. Related studies were identified from PubMed, EMBASE, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM). Pooled ORs and 95% CIs were used to assess the strengthof the associations. A total of 8 studies including 17834 subjects were involved in this meta-analysis. High selenium level was associated with GC risk in case-control study (OR = 0.62, 95% CI 0.44-0.89, P = 0.009; I2 = 52%) and cohort study (OR = 0.87, 95% CI 0.78-0.97, P = 0.01; I2 = 25%). In addition, high selenium level was associated with GC mortality risk (OR = 0.90, 95% CI 0.84-0.97, P = 0.006, I2 = 49%). In summary, this meta-analysis suggested that selenium might inversely associated with GC risk and GC mortality.

Prognostic value of peripheral blood lymphocyte-to-monocyte ratio in patients with solid tumors: a meta-analysis.

BACKGROUND: Although accumulating evidence suggests peripheral blood lymphocyte-to-monocyte ratio (LMR) could act as a prognosis predictor in various tumors, the prognostic value of LMR still remains controversial. We carried out this meta-analysis to evaluate the association of pretreatment LMR with survival outcomes in patients with solid tumors. METHODS: Eligible studies were collected and extracted by searching PubMed and Embase databases up to June 3, 2015. The pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) were computed to assess the prognostic value of LMR quantitatively. RESULTS: Eighteen studies with a total of 8,377 participants were enrolled in this meta-analysis. Our findings indicated that elevated pre-treatment LMR predicted a significantly favorable overall survival (HR=0.59, 95% CI: 0.53-0.67) and disease-free survival (HR=0.74, 95% CI: 0.68-0.80) in solid tumor patients. Subgroup analyses revealed that enhanced LMR was significantly associated with favorable overall survival in patients with digestive system cancers (HR=0.63, 95% CI: 0.49-0.81), urinary tract tumors (HR=0.66, 95% CI: 0.52-0.84), lung cancer (HR=0.62, 95% CI: 0.54-0.72), and nasopharyngeal carcinoma (HR=0.50, 95% CI: 0.43-0.57). CONCLUSION: This meta-analysis showed that enhanced LMR may indicate a favorable prognosis in patients with solid tumors.

Intratumoral Heterogeneity of Subcutaneous Nodules in a Never-Smoker Woman of Lung Squamous Cell Carcinoma Detected on 18F-Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography: A Case Report.

Subcutaneous tissue is a rare site of metastasis, accounting for only 1-2% of all lung neoplasms. Positron emission tomography (PET) using ¹8F-fluorodeoxyglucose (FDG) has been reported to increase the diagnostic accuracy of subcutaneous metastasis. A 58-year-old woman presented with complaints of dry coughing, in which three positive subcutaneous nodules were found on ¹8F-FDG positron emission tomography and computed tomography (PET/CT). Pathologic examination confirmed that each of the nodules contained 1) necrotic fat, 2) small amounts of blood cells and glandular epithelium, and 3) subcutaneous metastasis of moderately differentiated lung squamous cell carcinoma, respectively. Although PET/CT is useful for the detection of subcutaneous metastasis of primary lung cancer, we noted heterogeneous accumulation of ¹8F-FDG in subcutaneous tumors. This case highlights the importance of obtaining histological confirmation of malignant diseases whenever possible.

Morphological factors and cardiac doses in whole breast radiation for left-sided breast cancer.

BACKGROUND: To investigate the impact of the breast size, shape, maximum heart depth (MDH), and chest wall hypotenuse (the distance connecting middle point of the sternum and the length of lung draw on the selected transverse CT slice) on the volumetric dose to heart with whole breast irradiation (WBI) of left-sided breast cancer patients. MATERIALS AND METHODS: Fifty-three patients with left-sided breast cancer undergoing adjuvant intensity-modulated radiotherapy (IMRT) were enrolled in the study. The primary breast size and shape, MHD and DCWH (chest wall hypotenuse) were contoured on radiotherapy (RT) planning CT slices. The dose data of hearts were obtained from the dose-volume histograms (DVHs). Data were analyzed by one-way analysis of variance (ANOVA), Student's t-test and linear regression analysis. RESULTS: Breast size was independent of heart dose, whereas breast shape, MHD and DCWH were correlated with heart dose. The shapes of breasts were divided into four types, as the flap type, hemisphere type, cone type and pendulous type with heart mean dose being 491.8±234.6 cGy, 752.7±219.0 cGy, 620.2±275.7 cGy, and 666.1±238.0 cGy, respectively. The flap type of breasts shows a strong statistically reduction in heart dose, compared to others (p=0.008 for V30 of heart). DCWH and MHD were found to be the most important parameters correlating with heart dose in WBI. CONCLUSIONS: More attention should be paid to the heart dose of non-flap type patients. The MHD was found to be the most important parameter to correlate with heart dose in tangential WBI, closely followed by the DCWH, which could help radiation oncologists and physicsts evaluate heart dose and design RT plan in advance.

Preventive and therapeutic effects of quercetin on experimental radiation induced lung injury in mice.

OBJECTIVE: To investigate the protective effect of quercetin on radiation induced lung injury (RILI) and related mechanisms. MATERIALS AND METHODS: Mice treated with radiation and/or quercetin were sacrificed at 1-8 weeks after irradiation under anesthesia. Lung tissues were collected for histological examination. Immunohistochemistry (IHC) and Western blotting were performed to detect the protein expression of nuclear factor-κB (NF-κB) and Mitogen-activated protein kinases (MAPK) pathway. RESULTS: Hematoxylin and eosin (HE) staining showed that radiation controls displayed more severe lung damage than quercetin groups, either high or low dose. Results of IHC and Western blotting demonstrated the expression level of NF-κB to be decreased and that of an inhibitor of NF-κB (Iκb-α) to be increased by the quercetin intervention compared with the radiation control group. Numbers of JNK/SAPK, p38 and p44/p42 positive inflammatory cells were decreased in the radiation+quercetin injection group (P<0.05). CONCLUSIONS: Quercetin may play a radio-protective role in mice lung via suppression of NF-κB and MAPK pathways.

Interleukin-21 inhibits HBV replication in vitro.

BACKGROUND: Cytokines are crucial factors in the non-cytolytic antiviral process to inhibit HBV gene expression and replication. Interleukin (IL)-21 has been suggested to play an important role in HBV infection, but it remains unknown whether IL-21 can inhibit HBV replication or how it inhibits HBV replication. METHODS: In this study, we investigated the influence of IL-21 on HBV replication based on human hepatoma Huh7.93 cells co-cultured with human peripheral blood mononuclear cells (PBMCs) and the possible correlation among IL-21, interferon-γ, tumour necrosis factor-α and IL-10. RESULTS: We demonstrated that the decrease of IL-21 expression and the increase of IL-10 expression in PBMCs could promote HBV replication in vitro. We further revealed that IL-21 is not only able to effectively suppress HBV replication directly but also reduce HBV replication by inhibition of IL-10 secretion. CONCLUSIONS: Our results provide important evidence for the non-cytolytic antiviral mechanism mediated by cytokines and their interactions in chronic hepatitis B.

Carbon-carbon bond activation of cyclobutenones enabled by the addition of chiral organocatalyst to ketone.

The activation of carbon-carbon (C-C) bonds is an effective strategy in building functional molecules. The C-C bond activation is typically accomplished via metal catalysis, with which high levels of enantioselectivity are difficult to achieve due to high reactivity of metal catalysts and the metal-bound intermediates. It remains largely unexplored to use organocatalysis for C-C bond activation. Here we describe an organocatalytic activation of C-C bonds through the addition of an NHC to a ketone moiety that initiates a C-C single bond cleavage as a key step to generate an NHC-bound intermediate for chemo- and stereo-selective reactions. This reaction constitutes an asymmetric functionalization of cyclobutenones using organocatalysts via a C-C bond activation process. Structurally diverse and multicyclic compounds could be obtained with high optical purities via an atom and redox economic process.