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.

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.

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.

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.

Practical Pd(II)-Catalyzed C-H Alkylation with Epoxides: One-Step Syntheses of 3,4-Dihydroisocoumarins.

Pd(II)-catalyzed ortho-alkylation of benzoic acids with both terminal and internal epoxides affords 3,4-dihydroisocoumarins in one step. The presence of potassium countercations is crucial for this reaction. Monoprotected amino acid ligands significantly promote this reaction, enabling the development of a practical C-H alkylation reaction using 0.5 mol % Pd catalyst. The inversion of stereochemistry in the C-H alkylation step is consistent with a redox-neutral SN2 nucleophilic ring-opening process as opposed to a Pd(II)/Pd(IV) pathway.

Single-incision versus three-port laparoscopic appendectomy for acute appendicitis: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Three-port laparoscopic appendectomy (TPLA) has been shown superior to open appendectomy for acute appendicitis (AA); alternatively, single-incision laparoscopic appendectomy (SILA) is gaining popularity. The choice between SILA and traditional TPLA remains controversial. This meta-analysis of high-quality randomized controlled trials (RCTs) aims to compare efficacy and safety of SILA with TPLA for AA. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library for RCTs comparing SILA with TPLA. Reference lists of relevant articles and reviews, conference proceedings, and ongoing trial databases were also searched. Primary outcomes were operative time, postoperative complications, hospital duration, and days back to normal activities. Meta-analysis was conducted where possible comparing items using weighted mean differences (WMDs) and relative risks (RRs) according to type of data. Methodological quality was evaluated to assess bias risk. RESULTS: A total of 8 distinct RCTs comparing SILA (n = 616) with TPLA (n = 618) published from 2010 to 2013 were identified in our analysis. SILA took longer to conduct than TPLA (43 vs 38, WMD: 5.96, 95 % CI 2.54-9.38, P = 0.0006). Patients undergoing SILA needed more extra trocars addressed during operation (7 % vs 0 %, RR: 12.36, 95 % CI 3.83-39.90, P < 0.0001), but could return to full activities earlier (6 vs 7, WMD: -0.68, 95 % CI -1.10 to -0.26, P = 0.001). However, these differences were not clinically significant. All other parameters were comparable. CONCLUSIONS: These results provide level 1a support for the clinical similarity that SILA is basically as feasible, effective and safe as TPLA when dealing with AA, although statistically, SILA takes longer to perform, requires more extra trocars, and benefits patients with faster recovery compared with TPLA. Further RCTs are needed to update our finding with advancement of surgical techniques and skills.

Activated CD69+ T cells foster immune privilege by regulating IDO expression in tumor-associated macrophages.

Substantial evidence indicates that immune activation at stroma can be rerouted in a tumor-promoting direction. CD69 is an immunoregulatory molecule expressed by early-activated leukocytes at sites of chronic inflammation, and CD69(+) T cells have been found to promote human tumor progression. In this study, we showed that, upon encountering autologous CD69(+) T cells, tumor macrophages (MΦs) acquired the ability to produce much greater amounts of IDO protein in cancer nests. The T cells isolated from the hepatocellular carcinoma tissues expressed significantly more CD69 molecules than did those on paired circulating and nontumor-infiltrating T cells; these tumor-derived CD69(+) T cells could induce considerable IDO in monocytes. Interestingly, the tumor-associated monocytes/MΦs isolated from hepatocellular carcinoma tissues or generated by in vitro culture effectively activated circulating T cells to express CD69. IL-12 derived from tumor MΦs was required for early T cell activation and subsequent IDO expression. Moreover, we found that conditioned medium from IDO(+) MΦs effectively suppressed T cell responses in vitro, an effect that could be reversed by adding extrinsic IDO substrate tryptophan or by pretreating MΦs with an IDO inhibitor 1-methyl-DL-tryptophan. These data revealed a fine-tuned collaborative action between different types of immune cells to counteract T cell responses in tumor microenvironment. Such an active induction of immune tolerance should be considered for the rational design of effective immune-based anticancer therapies.

MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein.

The functional association between intronic miRNAs and their host genes is still largely unknown. We found that three gene loci, which produced miR-26a and miR-26b, were embedded within introns of genes coding for the proteins of carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase (CTDSP) family, including CTDSPL, CTDSP2 and CTDSP1. We conducted serum starvation-stimulation assays in primary fibroblasts and two-thirds partial-hepatectomies in mice, which revealed that miR-26a/b and CTDSP1/2/L were expressed concomitantly during the cell cycle process. Specifically, they were increased in quiescent cells and decreased during cell proliferation. Furthermore, both miR-26 and CTDSP family members were frequently downregulated in hepatocellular carcinoma (HCC) tissues. Gain- and loss-of-function studies showed that miR-26a/b and CTDSP1/2/L synergistically decreased the phosphorylated form of pRb (ppRb), and blocked G1/S-phase progression. Further investigation disclosed that miR-26a/b directly suppressed the expression of CDK6 and cyclin E1, which resulted in reduced phosphorylation of pRb. Moreover, c-Myc, which is often upregulated in cancer cells, diminished the expression of both miR-26 and CTDSP family members, enhanced the ppRb level and promoted the G1/S-phase transition. Our findings highlight the functional association of miR-26a/b and their host genes and provide new insight into the regulatory network of the G1/S-phase transition.

Metal-free [3 + 2 + 1]/[2 + 2 + 1] biscyclization: stereospecific construction with concomitant functionalization of indolizin-5(1H)-one.

A metal-free [3 + 2 + 1]/[2 + 2 + 1] biscyclization strategy has been developed for the stereospecific construction with concomitant derivation of biologically significant indolizin-5(1H)-ones from simple and commercial starting materials. The transformations are notable because they can yield five new σ bonds and six stereocenters including a quaternary carbon center in a single operation.

Switchable Copper-Catalyzed Approach to Benzodithiole, Benzothiaselenole, and Dibenzodithiocine Skeletons.

A copper-catalyzed reaction between 2-bromo-benzothioamides and S8 or Se involving sulfur rearrangement is reported, enabling access to benzodithioles 2 and benzothiaselenoles 6 in the presence of Cs2CO3. In the absence of S8 or Se, the reaction affords dibenzodithiocines 7 via two consecutive C(sp2)-S Ullmann couplings.

Long-Term Outcomes in Laparoscopic D2 Gastrectomy for Gastric Cancer: a Large Comprehensive Study Proposing Novel Hypotheses.

BACKGROUND: The long-term outcomes of laparoscopic gastrectomy (LG) versus open gastrectomy (OG) for gastric cancer (GC) remain obscure, especially for advanced cancer and disease affecting the upper stomach and in older patients. This study aimed to comprehensively assess the long-term efficacy of LG for GC using a large prospective database. METHODS: Totally, 1877 consecutive patients (1186 receiving LG and 691 OG) operated in 2004-2016 were analyzed, with a median follow-up of 63 months. Association of LG versus OG with disease-specific survival (DSS) and disease-free survival (DFS) overall and in various subgroups were investigated using multivariable Cox regression. Propensity score matching (PSM) was performed for sensitivity analysis. RESULTS: Before PSM, overall, there was no significant association of LG versus OG with survival after multivariable adjustment; however, in subgroup analyses, LG was associated with superior DSS in patients aged ≥ 70 years and those with upper GC. No significant associations regarding DFS were observed overall or in stratifications. PSM analyses revealed that LG was associated with better DSS also in patients aged ≥ 70 years (hazard ratio (HR) = 0.33, 95% confidence interval (CI) = 0.15-0.72) and in those with upper GC (HR = 0.51, 95% CI = 0.29-0.91), and with better DFS in those with upper GC (HR = 0.60, 95% CI = 0.37-0.99). Multivariable analysis showed that age, hepatitis B, performance status, tumor histology, stage, and vascular invasion were significantly associated with post-LG survival. LG-specific nomograms were then constructed with concordance indexes of 0.814 (DSS) and 0.809 (DFS) and excellent calibration. CONCLUSIONS: In this large institutional analysis, while LG for GC was associated with DSS and DFS similar to those for OG overall, non-inferior LG-associated survival especially DSS was observed in some subgroups rarely investigated in prospective or randomized settings. There could still be biases even after PSM due to confounders not accounted for in this observational study. However, these findings offer novel hypotheses for further validation.

Treatment of polycystic liver disease with resection-fenestration and a new classification.

AIM: To evaluate outcomes in patients with autosomal dominant polycyst liver disease (APLD) treated by combined hepatic resection and fenestration. A new classification was recommended to presume postoperative complications and long outcome of patients. METHODS: Twenty-one patients with APLD were treated by a combined hepatic resection and fenestration technique. All patients were reviewed retrospectively, and clinical symptoms, performance status and morbidity were recorded. A new classification of APLD is recommended here. RESULTS: All patients were discharged when free of symptoms. The mean follow-up time was 55.7 mo and three patients had a recurrence of symptoms at 81, 68 and 43 mo after operation, respectively. The overall morbidity rate was 76.2%. Two patients with Type B-II and Type B-I developed biliary leakage. Four patients had severe ascites, including three with Type B-III and one with Type B-II. Nine patients had pleural effusion, including one with Type A-I; one with Type B-I; five with Type B-II; one with Type A-III and one with Type B-III. Three patients with Type B had recurrence of symptoms, while none with Type A had severe complications. CONCLUSION: Combined hepatic resection and fenestration is an acceptable procedure for treatment of APLD. According to our classification, postoperative complications and long outcome can be predicted before surgery.

Laparoscopic surgery for gastric cancer: where are we now and where are we going?

INTRODUCTION: Minimally-invasive surgery is gaining increasing popularity for the management of gastric cancer (GC). Areas covered: The authors hereby comprehensively and systematically reviewed the randomized and/or prospective evidence on laparoscopic gastrectomy (LG) for GC. For early GC located in the distal stomach, various randomized trials have demonstrated the superiority/non-inferiority of LG especially in reducing surgical trauma and enhancing postoperative recovery without compromising surgical safety and oncologic efficacy. For advanced GC, while multicenter large-scale randomized evidence has demonstrated the safety and feasibility of LG by experienced hands, the long-term survival which is to be clarified by several ongoing trials are crucial to determine whether a more widespread application is acceptable. Randomized evidence regarding the application of laparoscopic total or proximal gastrectomy, which is technically challenging, is scarce. Various attempts in modification of the traditional laparoscopic approach to further reduce the trauma have been evaluated, such as single-incision and totally LG. LG is becoming increasingly individualized and precise. Expert commentary: The current randomized and/or prospective evidence supports the non-inferiority of laparoscopic surgery especially for the management of early GC located in the distal stomach, while the definitive efficacy of the laparoscopic approach for more surgically challenging situations remains largely explorative and investigative.

Morbidity and mortality of elderly patients with advanced gastric cancer after laparoscopy-assisted or open distal gastrectomy: a randomized-controlled trial.

Laparoscopy-assisted distal gastrectomy (LDG) combined with D2 lymphadenectomy may be safely performed in patients with advanced gastric cancer (AGC) by experienced surgeons at specialized high-volume institutions as shown in the Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS)-01. However, studies focusing on the use of LDG in patients with gastric cancer older than 65 years are rare. This study was designed to investigate the morbidity and mortality of elderly patients with gastric cancer who underwent laparoscopic-assisted or open distal gastrectomy (ODG). In this prospective, randomized, open, parallel controlled trial, patients older than 65 years with tumor located at the middle or lower part of the stomach will be enrolled in this study. Patients will be randomly divided into a laparoscopic group and an open surgery group. The early post-operative complications, intra-operative complications and post-operative recovery will be compared between the two groups. This trial will provide valuable clinical evidence for the objective assessment of the feasibility, short-term safety, and potential benefits of LDG compared with ODG for gastric cancer in the elderly patients. This trial has been registered on ClinicalTrials.gov. (Identifier: NCT02246153.) in September 22, 2014.

Short-Term Outcomes of Single-Incision Versus Conventional Laparoscopic Surgery for Colorectal Diseases: Meta-Analysis of Randomized and Prospective Evidence.

BACKGROUND: Conventional laparoscopic surgery (CLS) has been established as an alternative to open surgery for colorectal diseases (CRDs); simultaneously, single-incision laparoscopic surgery (SILS) is gaining popularity. OBJECTIVE: The aim of this study was to compare the short-term efficacy and safety of SILS with CLS for CRDs. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched for relevant randomized and prospective studies. Reference lists of relevant articles and reviews, conference proceedings, and ongoing trial databases were also screened. Outcome measures included surgical parameters, postsurgical recovery, pain, and adverse events. Meta-analysis was conducted where appropriate, comparing items using weighted mean differences (WMDs) and risk ratios (RRs) according to data type. RESULTS: A total of nine prospective (three randomized and six non-randomized) researches published from 2011 to 2015 were identified. The overall pooled results showed compared to CLS, SILS was associated with fewer blood transfusions, shorter incision length, and slighter postoperative pain, but more extra ports. All the other parameters were comparable. Randomized evidence supported SILS was associated with less blood loss, and shorter hospital stay, but longer operative time. For only colectomy cases, SILS was associated with more conversions to open surgery. SILS was associated with longer surgical time for Easterners, but not for Westerners. The detected differences were clinically insignificant. CONCLUSIONS: The results based on randomized and prospective evidence provide convincing support for the clinical similarity that SILS is basically as applicable, effective, and safe as CLS when dealing with colorectal lesions, but not for superiority.

A prospective appraisal of preoperative body mass index in D2-resected patients with non-metastatic gastric carcinoma and Siewert type II/III adenocarcinoma of esophagogastric junction: results from a large-scale cohort.

OBJECTIVE: To prospectively investigate associations of presurgical body mass index (BMI) with clinicopathological factors and its prognostic significance in radically D2-resected patients with non-metastasized gastric cancer (GC) and Siewert type II/III adenocarcinoma of esophagogastric junction (AEG). METHODS: A large prospective cohort consisting of radically-resected GC and AEG patients was analyzed. Follow-up was successful in 671 out of 700 patients, who were categorized into underweight (BMI<18.5), normal-weight (BMI=18.5-22.9), overweight (BMI=23-24.9), and obese (BMI≥25) groups according to Asian standards. BMI-associated factors were explored using multivariable logistic regression with adjustment. Cancer-specific survival analyses were conducted applying both univariable and multivariable Cox regression methods. RESULTS: Pre-operation, higher hemoglobin levels and smaller anemia proportions were observed in larger BMI groups. Higher BMI tended to be associated with higher neutrophil-lymphocyte ratios (NLRs). Patients with higher BMI had smaller tumors and more often stage I tumors, but longer surgical time and postsurgical stay. In multivariable analyses, higher hemoglobin levels, upper tumor location, poorer differentiation, and higher NLR were significantly associated with higher BMI. Overall, survival analyses revealed no significant role of BMI. However, in further stratifications after adjustment, compared to patients with normal BMI, obese patients had better survival in women, but worse in those with AEG; underweight was associated with reduced mortality risk in tumors differentiated well to moderately; overweight patients had increased death hazard when having thrombocytopenia. CONCLUSION: Overall, preoperative BMI had limited prognostic significance in operated GC patients. However, under specific conditions (e.g., female, AEG, good differentiation, and thrombocytopenia), BMI might indicate postoperative survival.

Interleukin-17-Producing Neutrophils Link Inflammatory Stimuli to Disease Progression by Promoting Angiogenesis in Gastric Cancer.

Purpose: Elevated levels of neutrophils have been associated with poor survival in various cancers, but direct evidence supporting a role for neutrophils in the immunopathogenesis of human cancers is lacking.Experimental Design: A total of 573 patients with gastric cancer were enrolled in this study. Immunohistochemistry and real-time PCR were performed to analyze the distribution and clinical relevance of neutrophils in different microanatomic regions. The regulation and function of neutrophils were assessed both in vitro and in vivoResults: Increased neutrophil counts in the peripheral blood were associated with poor prognosis in gastric cancer patients. In gastric cancer tissues, neutrophils were enriched predominantly in the invasive margin, and neutrophil levels were a powerful predictor of poor survival in patients with gastric cancer. IL17+ neutrophils constitute a large portion of IL17-producing cells in human gastric cancer. Proinflammatory IL17 is a critical mediator of the recruitment of neutrophils into the invasive margin by CXC chemokines. Moreover, neutrophils at the invasive margin were a major source of matrix metalloproteinase-9, a secreted protein that stimulates proangiogenic activity in gastric cancer cells. Accordingly, high levels of infiltrated neutrophils at the invasive margin were positively correlated with angiogenesis progression in patients with gastric cancer.Conclusions: These data provide direct evidence supporting the pivotal role of neutrophils in gastric cancer progression and reveal a novel immune escape mechanism involving fine-tuned collaborative action between cancer cells and immune cells in the distinct tumor microenvironment. Clin Cancer Res; 23(6); 1575-85. ©2016 AACR.

Organic chemistry. Functionalization of C(sp3)-H bonds using a transient directing group.

Proximity-driven metalation has been extensively exploited to achieve reactivity and selectivity in carbon-hydrogen (C-H) bond activation. Despite the substantial improvement in developing more efficient and practical directing groups, their stoichiometric installation and removal limit efficiency and, often, applicability as well. Here we report the development of an amino acid reagent that reversibly reacts with aldehydes and ketones in situ via imine formation to serve as a transient directing group for activation of inert C-H bonds. Arylation of a wide range of aldehydes and ketones at the ß or γ positions proceeds in the presence of a palladium catalyst and a catalytic amount of amino acid. The feasibility of achieving enantioselective C-H activation reactions using a chiral amino acid as the transient directing group is also demonstrated.

Identification of a novel TGF-ß-miR-122-fibronectin 1/serum response factor signaling cascade and its implication in hepatic fibrogenesis.

Transforming growth factor-ß (TGF-ß) is a potent cytokine that promotes the development of fibrogenic cells, stimulates the expression of fibrosis-related genes, and consequently results in hepatic fibrogenesis. The involvement of miRNAs in this process remains largely unknown. We showed that miR-122 was substantially expressed in hepatic stellate cells (HSCs) and fibroblasts, the major sources of fibrogenic cells in liver tissues. Notably, exposure to TGF-ß led to significant downregulation of miR-122. Furthermore, reintroduction of miR-122 suppressed TGF-ß-induced expression of fibrosis-related genes, including alpha smooth muscle actin (α-SMA), fibronectin 1 (FN1) and α1 type I collagen (COL1A1), in HSCs and fibroblasts. Subsequent mechanism investigations revealed that miR-122 directly inhibited FN1 expression by binding to its 3'-untranslated region and indirectly reduced the transcription of α-SMA and COL1A1 by inhibiting the expression of serum response factor (SRF), a key transcription factor that mediated the activation of fibrogenic cells. Further in vivo studies disclosed that intravenous injection of miR-122-expressing lentivirus successfully increased miR-122 level and reduced the amount of collagen fibrils, FN1 and SRF in the livers of CCl4-treated mice. These findings disclose a novel TGF-ß-miR-122-FN1/SRF signaling cascade and its implication in hepatic fibrogenesis, and suggest miR-122 as a promising molecular target for anti-fibrosis therapy.