Gastrointestinal perforation associated with bevacizumab in metastatic colorectal cancer.

OBJECTIVE: To investigate the risk factors for gastrointestinal perforation in metastatic colorectal cancer patients receiving bevacizumab. METHODS: We retrospectively reviewed 217 patients with metastatic colorectal cancer receiving bevacizumab to investigate the risk factors for gastrointestinal perforation. Three patients occurred intestinal perforation after receiving bevacizumab. We analyzed the clinical characteristics of three patients with intestinal perforation. RESULTS: All patients receiving bevacizumab. Three of 217 patients occurred intestinal perforation after receiving bevacizumab. Patient no. 1 was 70 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab. Patient no. 2 was 59 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation after receiving bevacizumab, and recovered smoothly after symptomatic treatment. Patient no. 3 was 60 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab. CONCLUSIONS: Patients with advanced colorectal cancer receiving bevacizumab are at risk of gastrointestinal perforation. The patient's age, gender and history of bowel obstruction may be associated with gastrointestinal perforation.

Immunoneoadjuvant therapy with immune checkpoint inhibitors of gastric cancer: an emerging exemplification : Immunoneoadjuvant therapy of gastric cancer.

Advances in immune checkpoint inhibitors (ICIs) have enabled more effective treatment for individuals with various types of solid tumors. Given the improved survival benefit and acceptable safety profile of ICIs in advanced gastric cancer, there is plenty of interest in the use of ICIs in the neoadjuvant setting with curative intent. Theoretically, immunoneoadjuvant with ICIs could boost the levels of endogenous tumor antigen present in the tumor to enhance T-cell priming and further enhance systemic immunity. This systemic immune response may improve the detection and elimination of the disseminated micrometastatic tumors beyond the resected tumor, which are sources of postsurgical relapse. Numerous clinical studies have begun to explore the application of ICIs in neoadjuvant treatment of gastric cancer. This article reviews the progress in the use of ICI monotherapy and in combination with alternative therapies for the treatment of gastric cancer to aid in the development of gastric cancer immunoneoadjuvant therapy and improve the overall therapeutic benefit.

Prognostic impact of portal area inflammation on intrahepatic cholangiocarcinoma patients without lymph node metastasis.

Background: Inflammation in the peritumoral normal tissues has impact on tumors. This study investigated the prognostic impact of portal area inflammation (PAI) on postoperative tumor recurrence and overall survival (OS) in patients undergoing resection for intrahepatic cholangiocarcinoma (ICC) without lymph node metastasis (LNM). Methods: Two hundred and ninety-seven patients who had undergone curative-intent resection at the Eastern Hepatobiliary Surgery Hospital, Shanghai, between 2011 and 2015 were selected. All patients were histologically diagnosed with ICC and had no LNM. PAI was defined by experienced pathologists based on standard pathological evaluations. Patients were divided into two groups according to the presence or absence of PAI. Further survival analysis was performed on PAI-related endpoints, OS, and recurrence-free survival (RFS), using Kaplan-Meier analysis and multivariate regression. Results: Among the 297 patients included in the study, the PAI incidence was 43.1% (128 patients). OS and RFS were worse in patients with PAI than in those without PAI (median OS, 21.87 months with PAI versus 33.37 months without PAI, P<0.001; median RFS, 12.33 months with PAI versus 21.60 months without PAI, P<0.001). Multivariate analysis revealed that PAI was an independent prognostic factor for both OS [hazard ratio (HR) 1.60; 95% confidence interval (CI): 1.18-2.17, P=0.003] and RFS (HR 1.40; 95% CI: 1.06-1.85, P=0.019). Conclusions: Consequently, PAI is a strong independent predictor of tumor recurrence and OS after curative-intent resection in patients with ICC without LNM. The impact of PAI on the postoperative prognosis of ICC patients without LNM is non-negligible. It is strongly recommended to pay attention to the inflammatory status of the portal area in ICC patients and increase the frequency of postoperative follow-up to improve the prognosis of ICC patients after curative resection.

Synthesis of Substituted of Benzo[4,5]imidazo[1,2-a]pyrimidines through (3 + 2+1) Cyclization of 2-Aminobenzimidazole, Acetophenone, and N,N-Dimethylformamide as One-Carbon Synthon.

An efficient method for the construction of benzo[4,5]imidazo[1,2-a]pyrimidines using N,N-dimethylformamide as a one-carbon source and 2-aminobenzimidazoles and acetophenone as substrates through a one-pot, three-component cascade reaction is described. Spectra investigations indicated the fluorescent properties of selected products, exhibiting quantum yields 0.07-0.16 with maxima absorption at 266-294 nm and emission at 472-546 nm.

A one-pot synthesis of 2,3-disubstituted-4(3H)-quinazolinone from o-aminobenzoic acid and DMF derivatives using imidazole hydrochloride as a promoter.

As a novel and environmentally friendly Brönsted acid, imidazole hydrochloride was used to promote the synthesis of 2,3-disubstituted-4(3H)-quinazolinone from o-aminobenzoic acid and DMF derivatives. The essence of this reaction is a multicomponent reaction, which constructs multiple chemical bonds between different components through the transamidation of imidazole hydrochloride. This protocol showed a wide range of functional group tolerance, and a series of quinazolinones were synthesized in low to moderate yields without metal catalysts, oxidants or other additives.

A rapid construction of 1,3,2-benzodiazaborininones [R-B(aam)] from boronic acids and anthranilamides.

A simple, efficient and mild methodology for the synthesis of 1,3,2-benzodiazaborininones [R-B(aam)] from boronic acids and anthranilamides on ethyl acetate is described. A series of 1,3,2-benzodiazaborininones were prepared in moderate to excellent yields at room temperature without dehydrating agents, metal catalysts, corrosive acids or other additives. Meanwhile, a multi-gram scale reaction is also performed to ensure the scalability of the reaction, and the product can be conveniently isolated by simple filtration.

Reactivities of silane coupling agents in the silica/rubber composites: Theoretical insights into the relationships between energy barriers and electronic characteristics.

Si69 and Si75, typical commodities of silane coupling agents, are often employed in tire recipes to work as the bridges connecting silica and polymers, with which rolling resistance and wet traction are enhanced without loss in abrasion resistance. In this article, the reactivities of Si69 and Si75 with silica and various rubbers were theoretically investigated by using density functional theory (DFT). When the agents were coupled with silica, not only the acid+water condition but also the pure acid condition was confirmed to readily trigger the condensation reactions. The corresponding Gibbs free energy barriers were related to the charge distributions of reaction regions. As the agents suffered from the homolysis of central SS bonds, the generated single-S-tailer radicals (RS·) showed significantly higher reactivities of both the radical addition and the α-H transfer reactions with rubbers, due to the stronger radical philicities of the terminal sulfur radicals with larger condensed local softnesses [s0 (S)]. When the agents underwent the heterolysis of central SS bonds, the terminal sulfur anions with smaller s- (S) indices, however, facilitated the nucleophilic addition reactions with rubbers. Several derivative indices based on the condensed local softnesses were also proposed here to shed light on the reactivities from the viewpoint of the relationship between energy barriers and electronic characteristics. The above findings pave the way for the design of new kinds of silane coupling agents using computer-aided techniques, and meanwhile, provide references for the practical application of Si69 and Si75 to the silica/rubbers systems.

A rapid construction of new boron heterocycles and evaluation of photophysical properties of iminoboronates.

A green and efficient method for the synthesis of oxadiazaborole, dioxazaborinine, and oxadiazaborinine from the reactions of phenylboronic acid with amidoxime, α-hydroxyl oxime and α-hydroxyl hydrazone, respectively, is described. The reactions were performed under catalyst-free and mild conditions. All products can be rapidly purified by filtration and washing. In addition, a set of iminoboronates were prepared following a one-pot multicomponent reaction procedure using α-hydroxyl hydrazone, salicylaldehyde and boronic acid derivatives as starting materials and their photophysical properties were assessed. Then, cross-coupling reactions can be carried out smoothly on some target compounds, which may help develop new boron masking strategies.

Imidazole Hydrochloride Promoted Synthesis of Nitriles from Aldehydes.

BACKGROUND AND OBJECTIVE: As a key pharmacophore, the cyano group widely exists in a variety of biologically active compounds. Besides, nitriles are also valuable intermediates for many common functional groups. In this current work, a new synthesis strategy was developed to obtain nitriles from aldehydes. METHODS: Using commercially available aldehydes as raw materials, and hydroxylamine and hydrochloride as nitrogen sources, the corresponding nitrile compounds were successfully synthesized by the one-pot method through the promotion of imidazole hydrochloride. And it was characterized by 1H NMR, 13C NMR, and mass spectrometry. RESULTS: Various reaction conditions were applied in order to find an optimum and convenient procedure for the formation of nitriles. The highest yields (95%) were achieved using sulfolane as a solvent, and imidazole hydrochloride as a promoter. CONCLUSION: In conclusion, we developed a new synthetic method for nitrile compounds from aldehydes. Twenty seven examples of functionalized nitrile compounds have been synthesized in good to excellent yields. This methodology features that an environmentally benign imidazole hydrochloride replaces transition metal catalysts and oxidants required in conventional strategies to convert aldehydes into nitriles with good functional group tolerability. Further exploration of imidazole hydrochloride is ongoing in our laboratory.

Development of personalized classifier based on metastasis and the immune microenvironment to predict the prognosis of osteosarcoma patients.

Background: Osteosarcoma is a common malignant bone tumor with a poor prognosis. The progression and metastasis of osteosarcoma are significantly influenced by the tumor microenvironment (TME). This study aimed to develop a personalized classifier based on metastasis and immune cells in the TME to achieve better prognostic prediction in osteosarcoma. Methods: Firstly, osteosarcoma metastasis-related differentially expressed genes (DEGs) and infiltrating immune cells in the TME were analyzed using a series of bioinformatics methods. The metastasis-related gene signature (MRS) and TME score of osteosarcoma patients were then developed. On this basis, a personalized MRS-TME classifier was constructed and validated in other clinical cohorts and different subgroups. In addition, the relationship between the MRS-related genes and the immune microenvironment was also clarified. Finally, the signaling pathways and immune response genes in osteosarcoma patients among different MRS-TME subgroups were analyzed to explore the underlying molecular mechanism. Results: We first identified the metastasis-related DEGs in osteosarcoma, which were primarily involved in the muscle system process, calcium ion homeostasis, cell chemotaxis, and leukocyte migration. A personalized MRS-TME classifier was then constructed by integrating the MRS (10 genes) and TME (six immune cells) scores. The MRS-TME classifier demonstrated a potent capacity of predicting the survival prognosis in diverse osteosarcoma cohorts as well as in the clinical feature subgroups. The MRS score was negatively associated with the TME score, and patients in the MRSlow/TMEhigh subgroup exhibited a better prognosis compared to all other subgroups. Significant differences existed between the cellular signaling pathways and immune response profiles among the different MRS-TME subgroups, especially in relation to the metabolism-related biological processes and the inflammatory response. Conclusions: The MRS-TME classifier might be a beneficial tool to aid in the prognostic evaluation and risk stratification of osteosarcoma patients.

Discovery of 2,4-pyrimidinediamine derivatives as potent dual inhibitors of ALK and HDAC.

Combination of anaplastic lymphoma kinase (ALK) inhibitor with histone deacetylases (HDAC) inhibitor could exert synergistically anti-proliferative effects on ALK positive non-small cell lung cancer (NSCLC) naïve or resistant cells. In this work, we designed and synthesized a series of 2,4-pyrimidinediamine derivatives as dual ALK and HDAC inhibitors based on pharmacophore merged strategy. Among which, compound 10f displayed the most potent and balanced inhibitory activity against ALK (IC50 = 2.1 nM) and HDAC1 (IC50 = 7.9 nM), respectively. In particular, 10f was also potent against the frequently observed Crizotinib-resistant ALKL1196M (IC50 = 1.7 nM) as well as the Ceritinib-resistant ALKG1202R (IC50 = 0.4 nM) mutants. In antiproliferative activity assay, 10f exhibited impressive activity on ALK-addicted cancer cell lines at low micromole concentrations, which was comparable to that of Crizotinib and Ceritinib. Further flow cytometric analysis indicated that 10f could effectively induce cell death via cell apoptosis and cell cycle arrest. Taken together, these results suggested 10f would be a promising lead compound for the ALK-positive NSCLC treatment, especially the Ceritinib- or Crizotinib-resistant NSCLC.

Synergistic impact of resection margin and microscopic vascular invasion for patients with HBV-related intrahepatic cholangiocarcinoma.

OBJECTIVES: The resection margin (RM) status and microscopic vascular invasion (MVI) are known prognostic factors for intrahepatic cholangiocarcinoma (ICC). An enhanced understanding of their impact on long-term prognosis is required to improve oncological outcomes. METHODS: A total of 711 consecutive patients who underwent curative liver resection for hepatitis B virus-related ICC were retrospectively analyzed. The different impact of the RM status (narrow, <1 cm, or wide, ≥1 cm) and MVI (positive, +, or negative, -) on overall survival (OS) and recurrence-free survival (RFS) were analyzed. RESULTS: The 1-, 3-, and 5-year OS rates were 67.6%, 42.5%, and 33.2% in wide RM & MVI (-), 58.0%, 36.1%, and 26.5% in narrow RM & MVI (-), 51.0%, 27.0%, and 24.3% in wide RM & MVI (+), and 39.0%, 20.4% and 14.3% in narrow RM & MVI (+) (p < 0.001). Multivariate analysis showed that RM & MVI were independent risk factors for the OS and RFS. CONCLUSION: Combined analysis of RM and MVI can better stratify the risks of postoperative death and recurrence in patients with HBV-related ICC, which may help subsequent adjuvant therapy and closer follow-up.

Electronic Spin Moment As a Catalytic Descriptor for Fe Single-Atom Catalysts Supported on C2N.

The electrocatalytic activity of transition-metal-based compounds is strongly related to the spin states. However, the underlying relationship connecting spin to catalytic activity remains unclear. Herein, we carried out density functional theory calculations on oxygen reduction reaction (ORR) catalyzed by Fe single-atom supported on C2N (C2N-Fe) to shed light on this relationship. It is found that the change of electronic spin moments of Fe and O2 due to molecular-catalyst adsorption scales with the amount of electron transfer from Fe to O2, which promotes the catalytic activity of C2N-Fe for driving ORR. The nearly linear relationship between the catalytic activity and spin moment variation suggests electronic spin moment as a promising catalytic descriptor for Fe single-atom based catalysts. Following the revealed relationship, the ORR barrier on C2N-Fe was tuned to be as low as 0.10 eV through judicious manipulation of spin states. These findings thus provide important insights into the relationship between catalytic activity and spin, leading to new strategies for designing transition metal single-atom catalysts.

Computational design of p-(dimethylamino)benzylidene-derived push-pull polyenes with high first-hyperpolarizabilities.

Multiple theoretical investigations on three new series of donor-bridge-acceptor substituted compounds are employed to aid in the design of NLO-phores with high first-hyperpolarizability ß. The effect of varying the acceptor (rhodanine, thiohydantoin and thiobarbituric acid derivative-based) and bridge parts of these D-π-A systems was analyzed in terms of geometric and optoelectronic parameters such as bond length alternation, ground state dipole moments, HOMO and LUMO energies, UV-vis absorption spectra, transition dipole moments, and electronic absorption energies. Various functionals with the AUG-cc-pVDZ basis set including B3LYP, PBE38, and ωB97XD, and the Hartree-Fock method were employed to calculate ß values, and the solvent effect was also considered by employing the SMD model. The variation of first-hyperpolarizabilities has been explained satisfactorily in terms of the PBE38/AUG-cc-pVDZ level calculated spectroscopic properties in the light of the sum-over-states method and the two-level model. The comprehensive study indicates that the most worthwhile targets for development as NLO-phores are compounds that include a longer π-bridge.

Michael Addition Reaction Catalyzed by Imidazolium Chloride to Protect Amino Groups and Construct Medium Ring Heterocycles.

An effective approach for amino protection and construction of a seven-membered ring has been developed. The method uses imidazolium chloride to carry out the Michael addition reaction at low temperatures and perform amino deprotection or construction of a seven-membered ring at high temperatures.

Enhanced Activity of C2N-Supported Single Co Atom Catalyst by Single Atom Promoter.

The remarkable chemical activity of metal single-atom catalysts (SACs) lies in their unique electronic states associated with the low-coordination nature of single-atom sites. Yet, electronic state manipulation normally requires direct contact with other atoms, which inevitably changes the low-coordination environment. Herein, we found by first-principle calculations that the activity of a Co SAC for HCOOH dehydrogenation is appreciably enhanced via electronic state manipulation by a noncontact single atom promoter. A Co atom and a Sn/Ge/Pb atom are anchored in the same cavity of a graphitic C2N monolayer. Surprisingly, the nonbonded promoter makes two far splitting spin states of Co almost degenerate via charge redistribution of C2N support. Further, the high-spin Co gives a remarkably low reaction barrier comparable to Pt or Pd catalysts. Our results demonstrate that the activity of a SAC can be tuned via a noncontact promoter, casting new insights into electronic state modulation of SACs on graphene-like support.

Eco-Friendly Syntheses of 2-Substituted Benzoxazoles and 2-Substituted Benzothiazoles from 2-Aminophenols, 2-Aminothiophenols and DMF Derivatives in the Presence of Imidazolium Chloride.

A simple, economical and metal-free approach to the synthesis of 2-substituted benzoxazoles and 2-substituted benzothiazoles from 2-aminophenols, 2-aminothiophenols and DMF derivatives, only using imidazolium chloride (50% mmol) as promoter without any other additive, was reported. Various 2-substituted benzoxazoles and 2-substituted benzothiazoles were thus prepared in moderate to excellent yields.

Synthesis and characterization of four process impurities in pazopanib.

Pazopanib (trade name Votrient®) is a potent and selective multi-targeted tyrosine kinase inhibitor that blocks tumor growth and inhibits angiogenesis. Based on a recently reported procedure, we herein report the first synthesis of four potential process impurities generated in the production of pazopanib. The structure of these impurities were synthesized and characterized by 1H NMR, 13C NMR and HRMS data. The possible formation mechanisms of these impurities were also elucidated. These findings should be useful for the quality control of pazopanib in manufacture.

Imidazolium Chloride: An Efficient Catalyst for Transamidation of Primary Amines.

A highly efficient and convenient protocol of imidazolium chloride (30 mol %) catalyzed amidation of amines with moderate to excellent yields was reported. The protocol shows broad substrate scope for aromatic, aliphatic, and heterocyclic primary amines.

Halogen-Metal Exchange on Bromoheterocyclics with Substituents Containing an Acidic Proton via Formation of a Magnesium Intermediate.

A selective and practical bromine-metal exchange on bromoheterocyclics bearing substituents with an acidic proton under non-cryogenic conditions was developed by a simple modification of an existing protocol. Our protocol of using a combination of i-PrMgCl and n-BuLi has not only solved the problem of intermolecular quenching that often occurred when using alkyl lithium alone as the reagent for halogen-lithium exchange, but also offered a highly selective method for performing bromo-metal exchange on dibrominated arene compounds through chelation effect.