Copper-Catalyzed Decarboxylation Cross-Coupling Cascade Reaction for Synthesis of Fused Dihydro-benzoxazinones.

A protocol for a tandem copper-catalyzed intermolecular decarboxylation cross-coupling cascade between o-bromobenzoic acids and proline or piperic acid has been disclosed. The developed protocol allows access to a variety of synthetically useful fused benzoxazinones scaffolds with high efficiency and good functional group compatibility. A mechanistically sequential approach for the decarboxylation and dehydration coupling process was presented.

NHC catalyzed radical tandem cyclization: an efficient synthesis of α,α-difluoro-γ-lactam derivatives.

Herein, an N-heterocyclic carbene (NHC) catalyzed radical tandem cyclization reaction of N-allylbromodifluoroacetamides and aldehydes has been developed. This method is an efficient protocol for synthesizing α,α-difluoro-γ-lactam derivatives in moderate to good yields (27 examples, up to 88% yield and 10 : 1 dr). This strategy features mild and metal-free conditions, high efficiency, and a broad substrate scope.

Overexpression of the telomerase holoenzyme induces EMT and tumorigenesis of HPV-immortalized keratinocytes.

Cervical cancer is the most frequent malignancy of the female genital tract and is associated with persistent infection of the uterine cervix with high-risk human papillomaviruses (HPV). The two HPV oncoproteins, E6 and E7, cooperatively immortalize cervical cells and are essential but insufficient for inducing tumorigenicity. During the progression of HPV-associated cervical dysplasia to carcinoma, the cellular telomerase reverse transcriptase (TERT) gene is activated and the TERC gene amplified. We questioned whether these increases in telomerase components might mediate the acquisition of the tumorigenic phenotype. We therefore transduced the TERT and TERC genes into E6/E7 immortalized keratinocytes that were anchorage-dependent and nontumorigenic. The resultant cells showed a profound morphological change characteristic of epithelial-mesenchymal transition as well as a corresponding increase in expression of vimentin, N-cadherin, Zinc finger E-Box binding homeobox 1, snail family transcriptional repressor 1 and matrix Metallopeptidase 2 and decrease in keratin and E-cadherin. More important, the transduced cells were now anchorage-independent and formed tumors in immunodeficient mice. Our findings indicate that overexpression of the telomerase holoenzyme in HPV-immortalized cells is sufficient to induce the complete transformed phenotype.

NHC-Catalyzed [2 + 4] Annulation of Alkynyl Ester with Chalcone.

An NHC-catalyzed [2 + 4] cyclization of alkynyl ester with α,ß-unsaturated ketone to form a pyran scaffold was developed successfully. The cheap and easily available starting materials, mild reaction conditions, moderate to excellent yields, and high atom economy make this strategy attractive for the syntheses of highly substituted 4H-pyran derivatives.

NHC-catalyzed [4 + 2] annulations of allenoates and 2,3-dioxopyrrolidine derivatives.

A facile NHC-catalyzed [2 + 4] annulation of allenoates with 2,3-dioxypyrrolidine derivatives was discovered, which paved a new avenue for the construction of highly substituted pyranopyrrole with moderate to good yields, high atom economy and mild reaction conditions.

Pd(II)-Catalyzed Arylation/Oxidation of Benzylic C-H of 8-Methylquinolines: Access to 8-Benzoylquinolines.

An efficient access to 8-benzoylquinoline was developed by a sequential arylation/oxidation of 8-methylquinolines with aryl iodides in the presence of Pd(OAc)2. This transformation demonstrates good tolerance of a wide range of functional groups on aryl iodides, providing good to excellent yields of 8-benzoylquinolines.

Impact of diabetes on prognosis of gastric cancer patients performed with gastrectomy.

OBJECTIVE: This study aimed to determine the impact of type 2 diabetes mellitus (T2DM) on clinical outcomes of gastric cancer (GC) patients and explore whether metformin use and good glycemic control could reverse it. METHODS: Clinicopathologic data of consecutive GC patients who underwent gastrectomy at Nanfang Hospital between October 2004 and December 2015 were included. Propensity score matching (PSM) was performed to balance the important factors of the disease status between non-T2DM and T2DM group. The last follow-up time was January 2019. RESULTS: A total of 1,692 eligible patients (1,621 non-T2DM vs. 71 T2DM) were included. After PSM, non-T2DM group (n=139) and T2DM group (n=71) were more balanced in baseline variables. The 5-year cancer-specific survival (CSS) rate in T2DM group (47.0%) was inferior to that in non-T2DM group (58.0%), but did not reach statistical significance [hazard ratio (HR)=1.319, 95% confidence interval (95% CI): 0.868-2.005, P=0.192]. While the 5-year progress-free survival (PFS) rate of T2DM group (40.6%) is significantly worse than that in non-T2DM group (56.3%) (HR=1.516, 95% CI: 1.004-2.290, P=0.045). Univariate and multivariate analyses showed that T2DM was an independent risk factor for PFS but not for CSS. In T2DM group, metformin use subgroup was associated with superior 5-year CSS and PFS in compared with non-metformin use subgroup, although the difference was not statistically significant (5-year CSS: 48.0%vs. 45.4%, HR=0.680, 95% CI: 0.352-1.313, P=0.246; 5-year PFS: 43.5%vs. 35.7%, HR=0.763, 95% CI: 0.400-1.454, P=0.406). The 5-year CSS rate was 47.5% in good glycemic control subgroup and 44.1% in poor glycemic control subgroup (HR=0.826, 95% CI: 0.398-1.713, P=0.605). And both two subgroups yielded a similar 5-year PFS rate (42.2%vs. 36.3%, HR=0.908, 95% CI: 0.441-1.871, P=0.792). CONCLUSIONS: DM promoted disease progress of GC after gastrectomy but had not yet led to the significant discrepancy of CSS. For GC patients with T2DM, metformin use was associated with superior survival but without statistical significance, while better glycemic control could not improve the prognosis.

Prognostic value and nomograms of proximal margin distance in gastric cancer with radical distal gastrectomy.

OBJECTIVE: The proximal margin (PM) distance for distal gastrectomy (DG) of gastric cancer (GC) remains controversial. This study investigated the prognostic value of PM distance for survival outcomes, and aimed to combine clinicopathologic variables associated with survival outcomes after DG with different PM distance for GC into a prediction nomogram. METHODS: Patients who underwent radical DG from June 2004 to June 2014 at Department of General Surgery, Nanfang Hospital, Southern Medical University were included. The first endpoints of the prognostic value of PM distance (assessed in 0.5 cm increments) for disease-free survival (DFS) and overall survival (OS) were assessed. Multivariate analysis by Cox proportional hazards regression was performed using the training set, and the nomogram was constructed, patients were chronologically assigned to the training set for dates from June 1, 2004 to January 30, 2012 (n=493) and to the validation set from February 1, 2012 to June 30, 2014 (n=211). RESULTS: Among 704 patients with pTNM stage I, pTNM stage II, T1-2, T3-4, N0, differentiated type, tumor size ≤5.0 cm, a PM of (2.1-5.0) cmvs. PM≤2.0 cm showed a statistically significant difference in DFS and OS, while a PM>5.0 cm was not associated with any further improvement in DFS and OSvs. a PM of 2.1-5.0 cm. In patients with pTNM stage III, N1, N2-3, undifferentiated type, tumor size >5.0 cm, the PM distance was not significantly correlated with DFS and OS between patients with a PM of (2.1-5.0) cm and a PM≤2 cm, or between patients with a PM >5.0 cm and a PM of (2.1-5.0) cm, so there were no significant differences across the three PM groups. In the training set, the C-indexes of DFS and OS, were 0.721 and 0.735, respectively, and in the validation set, the C-indexes of DFS and OS, were 0.752 and 0.751, respectively. CONCLUSIONS: It is necessary to obtain not less than 2.0 cm of PM distance in early-stage disease, while PM distance was not associated with long-term survival in later and more aggressive stages of disease because more advanced GC is a systemic disease. Different types of patients should be considered for removal of an individualized PM distance intra-operatively. We developed a universally applicable prediction model for accurately determining the 1-year, 3-year and 5-year DFS and OS of GC patients according to their preoperative clinicopathologic characteristics and PM distance.

Ligand-Free Copper(I)-Catalyzed Benzylic Acyloxylation of 2-Alkylpyridines under Aerobic Conditions.

A ligand-free copper(I)-catalyzed benzylic acyloxylation of 2-alkylpyridines with carboxylic acids was realized by using 1.0 atm of O2 as a green oxidant. The transformation provided a facile access to a wide range of N-heterocyclic esters through C-O bond formation, with broad substrate scope and good functional group tolerance. Preliminary mechanistic investigations showed that this protocol included a radical process.

Monodentate Transient Directing Group Assisted Pd-Catalyzed Direct Dehydrogenative Cross-Coupling of Benzaldehydes with Arenes toward 9-Fluorenones.

Commercially available 3,5-bis(trifluoromethyl)aniline was found to be a highly efficient monodentate transient directing group (MonoTDG) for the palladium-catalyzed direct dehydrogenative cross-coupling of benzaldehydes with arenes. A diverse set of symmetrical and unsymmetrical 9-fluorenones was readily obtained in yields of 32-72% along with excellent regioselectivities and broad functional group compatibility as well as high atom economy under mild conditions via a dual carbon-hydrogen (C-H) bond activation sequence.

An NHC-catalyzed, stereoselective α-functionalization of α,ß-unsaturated carboxylic acids through in situ activation.

An N-heterocyclic carbene (NHC)-catalyzed α-functionalization of the in situ activated α,ß-unsaturated carboxylic acids bearing γ-H was realized through formal [4 + 2] annulations with o-quinone methides, which paved a new avenue for the assembly and modification of the dihydrocoumarin scaffold in good yields with excellent diastereo- and enantioselectivities.

An enantioselective assembly of naphthopyran via NHC-catalyzed [3 + 3] annulation of bromoenal with ß-tetralone.

An asymmetric assembly of naphthopyran was realized via the N-heterocyclic carbene (NHC)-catalyzed formal [3 + 3] annulation of bromoenal and ß-tetralone. The key advantages of this protocol include ready availability of starting materials, mild reaction conditions, good yields and excellent enantioselectivities.

Base-promoted regiodivergent allylation of N-acylhydrazones with Morita-Baylis-Hillman carbonates by tuning the catalyst.

A regiodivergent allylation of N-acylhydrazones with Morita-Baylis-Hillman (MBH) carbonates has been developed, providing α- or γ-allylated products in excellent yields by using different catalysts. The nature of the base catalyst plays a pivotal role in controlling the reaction pathway, allowing regiospecific access to diverse allylic substituted target compounds from identical substrates.

Long-term outcomes of laparoscopy-assisted distal gastrectomy versus open distal gastrectomy for gastric cancer: a 10-year single-institution experience.

BACKGROUND: Laparoscopy-assisted distal gastrectomy (LADG) for gastric cancer has been widely applied; however, its oncologic efficacy has yet been well established. The study aimed to compare the long-term oncologic outcomes of LADG versus open distal gastrectomy (ODG) on gastric cancer. METHODS: The clinicopathologic data of gastric cancer patients who underwent distal gastrectomy with curative intent from October 2004 through September 2014 were included and analyzed in a retrospective cohort. The last follow-up was September 2016. RESULTS: 769 eligible patients (LADG 414 vs. ODG 355) were included in the study. No significant difference was observed between the groups in 5-year DFS (LADG 61.2% vs. ODG 59.1%; p = 0.384) and OS rates (LADG 65.8% vs. ODG 66.3%; p = 0.750). During surgery, though LADG group had longer operating time, the blood loss was less than ODG group. LADG group had faster postoperative recovery course including shorter time to oral intake, ambulation, and discharge time. Postoperative complication rate within 30 days showed no significant difference between the groups (LADG 15.7% vs. ODG 13.0%; p = 0.281). Age over 65 years old, blood loss > 200 ml, postoperative complication, and advanced T and N stage were identified as independent risk factors for DFS and OS. CONCLUSIONS: LADG could yield similar oncologic outcomes compared with ODG in treating distal gastric cancer. However, the findings need to be further confirmed through ongoing prospective randomized controlled trials.

ImmunoScore Signature: A Prognostic and Predictive Tool in Gastric Cancer.

OBJECTIVE: We postulated that the ImmunoScore (IS) could markedly improve the prediction of postsurgical survival and chemotherapeutic benefits in gastric cancer (GC). SUMMARY BACKGROUND DATA: A prediction model for GC patients was developed using data from 879 consecutive patients. METHODS: The expression of 27 immune features was detected in 251 specimens by using immunohistochemistry, and a 5-feature-based ISGC was then constructed using the LASSO Cox regression model. Testing and validation cohorts were included to validate the model. RESULTS: Using the LASSO model, we established an ISGC classifier based on 5 features: CD3invasive margin (IM), CD3center of tumor (CT), CD8IM, CD45ROCT, and CD66bIM. Significant differences were found between the high-ISGC and low-ISGC patients in the training cohort in 5-year disease-free survival (45.0% vs. 4.4%, respectively; P <0.001) and 5-year overall survival (48.8% vs. 6.7%, respectively; P <0.001). Multivariate analysis revealed that the ISGC classifier was an independent prognostic factor. A combination of ISGC and tumor, node, and metastasis (TNM) had better prognostic value than TNM stage alone. Further analysis revealed that stage II and III GC patients with high-ISGC exhibited a favorable response to adjuvant chemotherapy. Finally, we constructed 2 nomograms to predict which patients with stages II and III GC might benefit from adjuvant chemotherapy after surgery. CONCLUSIONS: The ISGC classifier could effectively predict recurrence and survival of GC, and complemented the prognostic value of the TNM staging system. Moreover, the ISGC might be a useful predictive tool to identify stage II and III GC patients who would benefit from adjuvant chemotherapy.

Reduced Port Laparoscopic Distal Gastrectomy with D2 Lymphadenectomy.

BACKGROUND: Reduced port laparoscopic surgery (RPLS), as a more minimally invasive treatment alternative to conventional laparoscopic surgery (CLS), has been increasing in recent years. 1 With the accumulation of surgical experience and improvements in surgical techniques, the indication of RPLS has been gradually extended from benign diseases to malignant tumors, including gastric cancer. 2-4 However, due to the lack of counteraction and triangulation, lymphadenectomy during reduced port laparoscopic gastrectomy (RPLG) for gastric cancer was considered challenging. In this study, we report our experience performing RPLG with D2 lymphadenectomy for distal gastric cancer. METHODS: A disposable, single-incision, multiport, laparoscopic surgery trocar was used through a 3-cm incision at the umbilicus for the laparoscopist and surgeon's right hand. One 12-mm trocar was inserted at the upper-right quadrant for the surgeon's left hand. Distal gastrectomy with D2 lymphadenectomy was performed in the same manner with CLS. 5 After extracting the resected specimen through the umbilicus incision, intracorporeal Roux-en-Y or B-II gastrojejunostomy was used for reconstruction. RESULTS: RPLG with D2 lymphadenectomy was performed on five patients from April 2017 to June 2017. No intraoperative event requiring conversion to CLS or open surgery occurred. No postoperative complication was observed. The median operating time and blood loss was 166 min and 50 ml. The mean number of retrieved lymph nodes was 32.7. Postoperatively, the mean time to first flatus, soft intake, and hospital stay was 2.6, 3.5, and 6.7 days respectively. CONCLUSIONS: RPLG with D2 lymphadenectomy might be safe and feasible in selected patients.

NHC-Catalyzed Hetero-Diels-Alder Reaction of Allenoate with Chalcone: Synthesis of Polysubstituted Pyranyl Carboxylate.

An NHC-catalyzed hetero-Diels-Alder and isomerization process of chalcones with allenoates was discovered, which furnished highly functionalized multisubstituted pyranyl carboxylates successfully. This method features a convergent assembly, mild reaction conditions, moderate to good yields, and high atom economy.

N-Heterocyclic Carbene-Catalyzed [4 + 2] Cyclization of Saturated Carboxylic Acid with o-Quinone Methides through in Situ Activation: Enantioselective Synthesis of Dihydrocoumarins.

An N-heterocyclic carbene (NHC)-catalyzed formal [4 + 2] synthesis of dihydrocoumarins was realized from saturated carboxylic acids and o-quinone methides via an in situ activation strategy. This protocol results in excellent diastereoselectivity and enantioselectivity and good yields and uses readily available and inexpensive starting materials.

NHC-catalyzed regiodivergent syntheses of difunctionalized 3-pyrazolidinones from α-bromoenal and monosubstituted hydrazine.

A formal [3 + 2] annulation of α-bromoenal with monosubstituted hydrazine could give 1,5 or 2,5-difunctionalized 3-pyrazolidinone regiodivergently by tuning the structure of the N-Heterocyclic Carbene (NHC) catalyst. Moderate to high yields, mild reaction conditions, good regioselectivity and potential biological significance of the final product have made this protocol attractive for the assembly of 3-pyrazolidinone.

NHC-catalyzed [4 + 2] annulation of 2-bromo-2-enals with acylhydrazones: enantioselective synthesis of δ-lactams.

An asymmetric assembly of δ-lactams was realized via the NHC-catalyzed formal [4 + 2] annulation of acylhydrazones and 2-bromo-2-enals bearing γ-H. The advantages of this protocol include high enantioselectivity, good yields, mild reaction conditions and potential biological significance of the final products.