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.

Direct syntheses of spiro- and fused-hydrofurans by a tunable tandem semipinacol rearrangement/oxa-Michael addition protocol.

A highly chemoselective one-pot reaction has been developed involving a tandem semipinacol rearrangement/oxa-Michael addition sequence in which the in situ generated ketol diene intermediate can be transformed specifically to either the spiro- or fused-dihydrofuran products (see scheme). This one-pot tandem reaction represents a general synthetic methodology for the syntheses of the two different kinds of furan derivatives.

Palladium-catalyzed cascade process to construct 1,2,5-trisubstituted pyrroles.

A novel palladium-catalyzed cascade allylic amination/intramolecular hydroamination/isomerization process of protected enynol 1 and primary amine 2 has been explored, which constructs the important 1,2,5-trisubstituted pyrroles. This transformation offers an alternative synthetic methodology capable of generating substituted pyrroles in a straightforward way.

The respiratory burst activity and expression of catalase in white shrimp, Litopenaeus vannamei, during long-term exposure to pH stress.

In this study, changes of reactive oxygen species (ROS) and the mRNA expression of catalase of the Pacific white shrimp, Litopenaeus vannamei, exposed to pH (5.4, 6.7, 8.0, and 9.3) stress was investigated at different stress time (24, 48, 72, 96, and 120 h). Level of malondialdehyde (MDA) in shrimp also were assessed. The results revealed that acidic (pH 5.4 and 6.7) or alkaline exposure (pH 9.3) induced production of ROS hemocytes and increase of MDA level in shrimp. Moreover, the catalase mRNA expression in hepatopancreas of L. vannamei was up-regulated in 24 h at pH 5.4, in 72 h at pH 6.7 and in 48 h at pH 9.3, whereas was down-regulated significantly after 72 h acidic (pH 5.4 and 6.7) or alkaline (pH 9.4) exposure. In the present study, there was the relationship between ROS and catalase mRNA expression under normal acidic and alkaline conditions. At pH 8, the increase of catalase transcripts due to up-regulation by ROS, whereas MDA level did not significantly change, suggesting activation of corresponding protective mechanisms of detoxifying ROS is essential for the proper functioning of cells and the survival of shrimps.

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.

Total synthesis of malyngamides K, L, and 5''-epi-C and absolute configuration of malyngamide L.

An accelerated, enantioselective, and general synthetic route to a class of malyngamides, K (1), L (3), and 5''-epi-C (4), bearing a cyclohexenone ring or a heavily oxygenated six-membered ring and a vinyl chloride structural motif was developed. The key step was the Suzuki cross-coupling reaction of boronic acids 6-8 with unsaturated carboxylic amides 5a,b possessing the chlorovinyl iodide functionality for the construction of the skeletons of 1-4. The key intermediates 10a,b were prepared using Ogilvie's method for the construction of the chlorovinyl iodide functionality. The NMR data of the synthetic compound 2 were in full agreement with those of the reported product, and the discrepancy in the specific rotation data suggested that the correct structure of malyngamide L should be 3, in which the absolute configuration of the amine part was enantiomeric to that in compound 2. Then the absolute configuration of the stereogenic center at C(3'') and C(4'') in malyngamide L was confirmed by synthesis of compound 3.

Phase I study of concurrent selective lymph node late course accelerated hyper-fractionated radiotherapy and pemetrexed, cisplatin for locally advanced esophageal squamous cell carcinoma.

The optimized concurrent chemoradiotherapy has not been established for patients with advanced esophageal squamous cell carcinoma (SCC). The aim of the present study was to evaluate the safety and efficacy of concurrent chemotherapy and selective lymph node (SLN) late course accelerated hyperfractionated (LCAF) intensity modulated radiotherapy (IMRT) for the patients with thoracic SCC. Twelve patients with T3-4N0-1M0-1a thoracic esophageal SCC were included. The total dose of SLN LCAF IMRT was 59.6 Gy/34 fractions in 5.4 weeks. The concurrent chemotherapy protocol was as following: cisplatin 10 mg/m(2) on days 1-5 and 22-26, pemetrexed in escalating doses, from the base level of 500 mg/m(2) once every 21 days. The primary objectives were to determine the maximum tolerated dose (MTD), recommended dose (RD), and dose limiting toxicities (DLTs). Secondary end point included determination of preliminary radiographic response rates. As a result, three patients were enrolled in dose level 1 with pemetrexed 500 mg/m(2) and nine patients in dose level 0 with 400 mg/m(2) , respectively. At dose level 1, DLTs occurred in two of three patients. However, only two of nine patients in Level 0 developed DLTs. The complete response and partial response were observed in eight and four patients, respectively. Furthermore, no patient experienced cancer progression with a median follow-up of 9 months. In conclusion, the concurrent SLN LCAF IMRT and chemotherapy is feasible. The MTD of pemetrexed in this regimen was 500 mg/m(2) and RD was 400 mg/m(2) . Although toxicities were common, the protocol was safe, well tolerated, and achieved an encouraging outcome.

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.

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.

[Impact of the pattern of lymph node metastasis on the clinical target volume in radiotherapy for thoracic esophageal squamous cell carcinoma].

OBJECTIVE: To study the pattern of lymph node metastasis of thoracic esophageal squamous cell carcinoma (ESCC) after esophagectomy and its impact on the clinical target volume (CTV) delineation in radiotherapy fpr thoracic ESCC. METHODS: The pattern of lymph node metastasis was retrospectively analyzed in 1077 patients with primary thoracic ESCC. All patients received esophagectomy with two- or three-field lymphadenectomy. The clinicopathologic factors related to lymph node metastasis were then analyzed using logistic regression analysis. RESULTS: The rates of cervical, upper mediastinal, middle mediastinal, lower mediastinal and abdominal cavity lymph node metastasis were 16.7%, 33.3%, 11.1%, 5.6% and 5.6%, respectively. The rates of those node metastasis in the middle thoracic ESCC were 4.0%, 3.8%, 28.5%, 7.1% and 17.1%, respectively, and the rates of those node metastasis in the lower thoracic ESCC were 1.5%, 3.0%, 22.7%, 37.0% and 33.2%, respectively. The depth of tumor invasion, histologic differentiation and the length of tumor were showed to be statistically most significant risk factors of lymph node metastasis of ESCC (P < 0.001). CONCLUSION: The depth of tumor invasion, histologic differentiation, and length of tumor were closely correlated with lymph node metastasis of ESCC. All these factors and tumor location should be considered comprehensively when designing the target volume for radiotherapy.

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.

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.

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.

[CT and MRI image fusion in three-dimensional conformal radiotherapy for cranial carcinoma].

OBJECTIVE: To investigate the advantage of CT and MRI image fusion in determining the target precisely during 3-dimensional conformal radiotherapy for cranial carcinoma. METHODS: Twenty-five patients received CT and MRI examination simultaneously for localizing the tumor and defining target before 3-dimensional conformal radiotherapy. The target defined by MRI image was used as gross tumor volume, whereas CT value was used to calculate dose, making plan for radiotherapy. The difference between the target defined by CT and MRI was compared. RESULTS: All the 25 patients underwent CT and MRI image fusion for localizing the tumor and defining the target in order to make anatomic symbol and surface symbol superposed. The number of tumor nodual detected by CT was as same as that found by MRI in 23 cases except two. Compared with the GTV defined by MRI image, it was larger in 10 cases by CT image, whereas smaller in 15 cases. The response rate assessed by MRI image was 64.0% (CR + PR) at the end of radiotherapy. CONCLUSION: CT and MRI image fusion technique is more precise than either by CT or MRI alone in defining the GTV of 3-dimensional conformal radiotherapy for cranial carcinoma.

[Processing of interferogram symmetrization in optical fiber Fourier spectrometer].

The asymmetry of an interferogram is caused by off-center sampling or defects in the fiber interferometer, and the spectra from Fourier cosine transformations of one-sided interferogram have phase errors. A method was firstly applied to symmetrizing interferogram by using the convolution technique in optical fiber Fourier spectrometer (FFTS). The phase error can be derived from the central portion of the interferogram. Symmetrization function was obtained from the Fourier transform of the phase error. Thus in spatial domain the symmetrization function convolved with original interferogram, and the spectra with correction of phase errors resulted from the symmetrized interferogram. Experimental study shows that the method efficiently corrects the phase error in FFTS. The method not only overcomes the disadvantages of two-sided interferogram, but also has better accuracy of the results.

[Protective effects and its mechanisms of total alkaloids from rhizoma Coptis chinensis on Helicobacter pylori LPS induced gastric lesion in rats].

OBJECTIVE: To study the effects and its possible mechanisms of total alkaloids (TA) from rhizoma Coptis chinensis on H. pylori LPS induced gastric lesion in rats. METHOD: H. pylori lipopolysaccharide was applied to rat intragastrically for 4 days to induce a pattern of mucosal responses resembling that of acute gastritis. After treatment with 50, 100, 200 mg x kg(-1) TA, we identified the changes on gastric histopathology, the effects on the activities of cNOS and NOS-2, the contents of TNF-alpha and the gastric mucus epithelial cell apoptosis. RESULT: H. pylori LPS could significantly induce the epithelial cell apoptosis of gastric mucus, increase the expression of NOS-2 and decline the expression of cNOS, and enhance the content of TNF-alpha in serum. Treatment with 50, 100, 200 mg x kg(-1) TA led to reduction in the extent of mucosal inflammatory changes elicited by H. pylori LPS and decrease in epithelial cell apoptosis. Furthermore, this effect of TA was associated with decrease in content of TNF-alpha in serum, decline in NOS-2, and increase in cNOS. CONCLUSION: The findings suggest that TA is a potent protective agent against H. pylori LPS induced gastric mucosal inflammation. The concerned mechanisms may be related to its inhibition on epithelial cell apoptosis, and the suppression of the inflammatory responses by upregulating cNOS and interfering with the events propagated by NOS-2, and reducing the content of TNF-alpha.

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.

[Impact of PET/CT on precise radiotherapy planning for non-small cell lung cancer].

OBJECTIVE: To investigate the impact of PET/CT on the clinical staging, target volume delineation and precise radiotherapy (PAR) planning for patients with non-small cell lung cancer (NSCLC). METHODS: PET/CT scanning was performed in 58 histologically proven NSCLC patients for radical radiotherapy or surgery. The clinical staging of all patients was determined by PET/CT according to 1997 World Health Organization (WHO) staging system. The gross tumor volume (GTV) was delineated and three-dimensional conformal radiotherapy (3D-CRT) planning was established with identical parameters based on CT image and PET/CT fused image, respectively. The indexes including volume of GTV (V(GTV)), percentage of the total lung volume which received more than 20 Gy (V(20)), mean lung dose (MLD), tumor control probability (TCP), normal tissue complication probability (NTCP), and dose to spinal cord (Ds) were selected and evaluated. The quality of the two plans and the impact of PET/CT on PAR planning was compare and analyzed. RESULTS: 1. PET/CT image results changed the clinical stages in 21 of 58 (36.2%) patients with 14 upstaged and 7 downstaged, therefore, the management decisions were modified in 16 (27.6%) patients. 2. Among 32 patients who underwent surgery, PET/CT staging result was consistent with pathologic staging in 29 with one false negative and 2 false positive in lymph node staging. The sensitivity of PET/CT was 96.9% and accuracy 90.6%. 3. The differences of indexes including V(GTV) (P = 0.004), V(20) (P = 0.000) and MLD (P = 0.004) between the two radiotherapy plannings were statistically significant, whereas, the Ds, TCP and NTCP (left lung, right lung, skin and spinal cord) was not. CONCLUSION: 1. The impact PET/CT on clinical staging of NSCLC and PAR planning was remarkable. 2. PET/CT is more consistent with pathology in staging than CT and, therefore, is an important compensatory staging measure. 3. Compared with CT, PET/CT can reduce the V(GTV) in patients with atelectasis and obstructive pneumonitis when contouring the target volume, so can provide better protection for normal surrounding lung tissue. On the other hand, PET/CT is more sensitive in detecting mediastinal lymph node metastasis than CT, and the V(GTV) can be more precise and guaranteed. 4. Radiopneumonitis may be more effectively prevented because of significant decrease in V(20) and MLD by more precise planning based on PET/CT results. 5. PET/CT not only can provide satisfactory Ds, TCP and NTCP within clinical demand, but also more precise delineation of the radiation target volume and precise radiotherapy planning for NSCLC.