PD-1 blockade plus COX inhibitors in dMMR metastatic colorectal cancer: Clinical, genomic, and immunologic analyses from the PCOX trial.

BACKGROUND: Approximately 20% of patients with DNA mismatch repair deficiency (dMMR) metastatic colorectal cancer do not respond to anti-programmed death-1 (PD-1) ligand therapy, and baseline biomarkers of response are lacking. METHODS: We conducted a phase 2 study to evaluate the efficacy of cyclooxygenase (COX) inhibitors in combination with anti-PD-1 therapy in patients with dMMR metastatic colorectal cancer. The primary endpoint was objective response rate. The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate, duration of response, and safety. FINDINGS: A total of 30 patients were enrolled, and the objective response rate was 73.3%, meeting the predefined endpoint of 68%. The median PFS and median OS were not reached at a median follow-up period of 50.8 months. Disease control was achieved in 28 patients (93.3%). The median duration of response was not reached. The combination was well tolerated. Multiomics analysis revealed that the antigen processing and presentation pathway was positively associated with treatment response and PFS. Higher TAPBP expression was predictive of better PFS (log-rank p = 0.003), and this prognostic significance was confirmed in an immunotherapy validation cohort. CONCLUSIONS: Thus, COX inhibitors combined with PD-1 blockade may be effective and safe treatment options for patients with dMMR metastatic colorectal cancer, and TAPBP may serve as a biomarker for immune checkpoint inhibitor therapy (this study was registered at ClinicalTrials.gov: NCT03638297). FUNDING: Funded by the National Natural Science Foundation of China (81974369) and the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004).

Borataalkenes, boraalkenes, and the η2-B,C coordination mode in coordination chemistry and catalysis.

Borataalkenes and boraalkenes are the boron-containing isoelectronic analogues of alkenes and vinyl cations respectively. Compared with alkenes, the borataalkene and boraalkene ligand motifs in transition metal coordination chemistry are relatively underexplored. In this review, the synthesis of borataalkene and boraalkene complexes and other transition metal complexes featuring the η2-B,C coordination mode is described. The diversity of coordination modes and geometry in these complexes, and the spectroscopic and structural evidence supporting their assignments is disclosed as well as computational analysis of bonding. The applications of the borataalkene ligand motif in synthetic organic homogeneous catalysis, especially those involving geminal bis(pinacolatoboronates) and 1,4-azaborines, are discussed.

Identification of immune cell infiltration landscape for predicting prognosis of colorectal cancer.

Background: The tumor microenvironment plays an essential role in the therapeutic response to immunotherapy. It is necessary to identify immune cell infiltration (ICI) subtypes for evaluating prognosis and therapeutic benefits. This study aimed to evaluate the ICI score as an effective prognostic biomarker for immune response. Methods: The cell-type identification by estimating relative subsets of RNA transcripts and the estimation of stromal and immune cells in malignant tumors using expression methods were used to analyse ICI landscapes in 161 colorectal cancer (CRC) samples with patients' clinical and prognostic data, RNA sequencing data, and whole-exome sequencing data from the Sixth Affiliated Hospital, Sun Yat-sen University (Guangzhou, China). Statistical analysis and data processing were conducted to calculate ICI scores, and to analyse the prognosis of CRC patients with different ICI scores and other features. A similar analysis with RNA sequencing and clinical data of colon adenocarcinoma (COAD) samples from The Cancer Genome Atlas (TCGA) database was conducted to confirm the correctness of the findings. Results: The high-ICI score group with a better prognosis (hazard ratio [HR], 2.19; 95% confidence interval [CI], 1.03-4.64; log-rank test, P = 0.036) was characterized by the increased tumor mutational burden and interleukin-17 (IL-17) signaling pathway. Significant differences in the prognosis and the expression levels of immune checkpoints and chemokine marker genes were found between the two ICI score groups. For COAD samples from TCGA, the results also showed a significant difference in patients' prognosis between the two ICI score groups (HR, 1.72; 95% CI, 1.00-2.96; log-rank test, P = 0.047). Conclusions: Tumor heterogeneity induced differences in identifying ICI subtypes of CRC patients. The ICI score may serve as an effective biomarker for predicting prognosis, help identify new therapeutic markers for CRC, and develop novel effective immune checkpoint blockade therapies.

Mechanism of Pd/Senphos-Catalyzed trans-Hydroboration of 1,3-Enynes: Experimental and Computational Evidence in Support of the Unusual Outer-Sphere Oxidative Addition Pathway.

The reaction mechanism of the Pd/Senphos-catalyzed trans-hydroboration reaction of 1,3-enynes was investigated using various experimental techniques, including deuterium and double crossover labeling experiments, X-ray crystallographic characterization of model reaction intermediates, and reaction progress kinetic analysis. Our experimental data are in support of an unusual outer-sphere oxidative addition mechanism where the catecholborane serves as a suitable electrophile to activate the Pd0-bound 1,3-enyne substrate to form a Pd-η3-π-allyl species, which has been determined to be the likely resting state of the catalytic cycle. Double crossover labeling of the catecholborane points toward a second role played by the borane as a hydride delivery shuttle. Density functional theory calculations reveal that the rate-limiting transition state of the reaction is the hydride abstraction by the catecholborane shuttle, which is consistent with the experimentally determined rate law: rate = k[enyne]0[borane]1[catalyst]1. The computed activation free energy ΔG‡ = 17.7 kcal/mol and KIE (kH/kD = 1.3) are also in line with experimental observations. Overall, this work experimentally establishes Lewis acids such as catecholborane as viable electrophilic activators to engage in an outer-sphere oxidative addition reaction and points toward this underutilized mechanism as a general approach to activate unsaturated substrates.

Distinct Clinicopathological Features and Prognostic Values of High-, Low-, or Non-Expressing HER2 Status in Colorectal Cancer.

The encouraging effects of HER2-ADC in patients with HER2-low expression cancers indicated the classical classifications based on positive and negative HER2 might no longer be suitable. However, the biology and prognosis of colorectal cancer patients with different HER2 expression status were still not clear. This is a multi-center retrospective study that included patients with histologically confirmed colorectal cancer and determined HER2 status who received radical surgical resection. HER2 immunohistochemistry (IHC) 1+ and IHC 2+ groups were combined and defined as a HER2-low group because of the concordance of clinicopathological characteristics. As compared with the HER2-high group, both the HER2-zero and the HER2-low group had less tumor with perineural invasion (14.3%, 13.1% vs. 31.6%, p = 0.001 and p < 0.001), less stage III disease (41.8%, 39.9% vs. 56.1%, p = 0.044 and p = 0.022), more RAS/BRAF mutation (52.1%, 49.9% vs. 19.5%, p < 0.001 and p < 0.001) and better disease-free survival (DFS) (3y-DFS rate of 78.7%, 82.4% vs. 59.3%, p < 0.001 and p < 0.001). Multivariate analysis and propensity score matching also revealed that HER2-high expression was an independent prognostic factor of DFS. In conclusion, our study revealed that HER2-low colorectal cancer tumors are close to HER2-zero tumors, but different from HER2-high tumors. The routine examination of HER2 IHC is needed in early-stage colorectal cancer.

Contribution of insurance status to the association between marital status and cancer-specific survival: a mediation analysis.

OBJECTIVES: To evaluate the extent to which marriage influences cancer-specific survival (CSS) by influencing the insurance status among patients with common solid cancers and the feasibility of reducing the survival gap caused by marriage by increasing private insurance coverage for unmarried patients. SETTING: A retrospective cohort study with patients retrieved from the Surveillance, Epidemiology and End Results programme. PARTICIPANTS: Patients with nine common solid cancers diagnosed between 2007 and 2016 were included. Patients were excluded if their marital status, insurance status, socioeconomical status, stage or cause of death was unavailable, if survival time was less than 1 month, or if they were younger than 18 years at the time of diagnosis. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was CSS, which was compared between married and unmarried individuals. Mediation analyses were conducted to determine the contribution of insurance status to the association between marriage and CSS. RESULTS: Married patients had better CSS than those unmarried (time ratio 1.778; 95% CI 1.758 to 1.797). Private health insurance was a key factor mediating the association between marital status and CSS (proportion mediated (PM), 17%; 95% CI 17% to 17.1%). The PM ranges from 10.7% in prostate cancer to 20% in kidney cancer. The contribution of private insurance to the association between marital status and CSS was greater among women than among men (PM 18.5% vs 16.7%). The mediating effect of private insurance was the greatest for the comparison between married and separated individuals (PM 25.6%; 95% CI 25.3% to 25.8%) and smallest for the comparison between married and widowed individuals (PM 11.0%; 95% CI 10.9% to 11.1%). CONCLUSIONS: 17% of the marital disparities in CSS are mediated by private insurance coverage. Increasing private insurance coverage for unmarried patients may reduce the survival gap related to marital status and sex. However, it is unclear whether better publicly funded insurance would have the same effect.

Enhancing unsupervised medical entity linking with multi-instance learning.

BACKGROUND: A lot of medical mentions can be extracted from a huge amount of medical texts. In order to make use of these medical mentions, a prerequisite step is to link those medical mentions to a medical domain knowledge base (KB). This linkage of mention to a well-defined, unambiguous KB is a necessary part of the downstream application such as disease diagnosis and prescription of drugs. Such demand becomes more urgent in colloquial and informal situations like online medical consultation, where the medical language is more casual and vaguer. In this article, we propose an unsupervised method to link the Chinese medical symptom mentions to the ICD10 classification in a colloquial background. METHODS: We propose an unsupervised entity linking model using multi-instance learning (MIL). Our approach builds on a basic unsupervised entity linking method (named BEL), which is an embedding similarity-based EL model in this paper, and uses MIL training paradigm to boost the performance of BEL. First, we construct a dataset from an unlabeled large-scale Chinese medical consultation corpus with the help of BEL. Subsequently, we use a variety of encoders to obtain the representations of mention-context and the ICD10 entities. Then the representations are fed into a ranking network to score candidate entities. RESULTS: We evaluate the proposed model on the test dataset annotated by professional doctors. The evaluation results show that our method achieves 60.34% accuracy, exceeding the fundamental BEL by 1.72%. CONCLUSIONS: We propose an unsupervised entity linking method to the entity linking in the medical domain, using MIL training manner. We annotate a test set for evaluation. The experimental results show that our model behaves better than the fundamental model BEL, and provides an insight for future research.

Assessment of Modifiable Factors for the Association of Marital Status With Cancer-Specific Survival.

Importance: Married patients with cancer have better cancer-specific survival than unmarried patients. Increasing the early diagnosis and definitive treatment of cancer among unmarried patients may reduce the survival gap. Objectives: To evaluate the extent to which marriage is associated with cancer-specific survival, stage at diagnosis, and treatment among patients with 9 common solid cancers and to recommend methods for reducing the survival gap. Design, Setting, and Participants: This retrospective, population-based cohort study included patients older than 18 years who were diagnosed with 1 of 9 common cancers between January 1, 2007, and December 31, 2016. Patient data were retrieved from the Surveillance, Epidemiology, and End Results Program. Statistical analyses were performed from August 1 to October 1, 2020. Exposures: Marital status, classified as married and unmarried (including single, separated, divorced, widowed, and unmarried patients or domestic partners). Main Outcomes and Measures: The primary outcome was the time ratio (TR) of cancer-specific survival (married vs unmarried). Mediation analyses were conducted to determine the extent to which the association of marriage with cancer-specific survival was mediated by stage at diagnosis and treatment. Results: This study included 1 733 906 patients (894 379 [51.6%] women; 1 067 726 [61.6%] married; mean [SD] age, 63.76 [12.60] years). Multivariate analyses found that those who were married were associated with better cancer-specific survival than unmarried patients (TR, 1.36; 95% CI, 1.35-1.37). Early diagnosis in breast cancer, colorectal cancer, endometrial cancer, and melanoma mediated the association between marital status and cancer-specific survival (breast cancer: proportion mediated [PM], 11.4%; 95% CI, 11.2%-11.6%; colorectal cancer: PM, 10.9%; 95% CI, 10.7%-11.2%; endometrial cancer: PM, 12.9%; 95% CI, 12.5%-13.3%; melanoma: PM, 12.0%; 95% CI, 11.7-12.4%). Surgery mediated the association between marital status and cancer-specific survival in lung (PM, 52.2%; 95% CI, 51.9%-52.4%), pancreatic (PM, 28.9%; 95% CI, 28.6%-29.3%), and prostate (PM, 39.3%; 95% CI, 39.0%-39.6%) cancers. Chemotherapy mediated the association of marital status with cancer-specific survival in lung (PM, 37.7%; 95% CI, 37.6%-37.9%) and pancreatic (PM, 28.6%; 95% CI, 28.4%-28.9%) cancers. Improved cancer-specific survival associated with marriage was greater among men than women (men: TR, 1.27; 95% CI, 1.25-1.28; women: TR, 1.20; 95% CI, 1.19-1.21). The contribution of receiving an early diagnosis and treatment with surgery or chemotherapy to the association between marital status and cancer-specific survival was greater among men than women (early diagnosis: PM, 21.7% [95% CI, 21.5%-21.9%] vs PM, 20.3% [95% CI, 20.2%-20.4%]; surgery: PM, 26.6% [95% CI, 26.4%-26.7%] vs PM, 11.1% [95% CI, 11.0%-11.2%]; chemotherapy: PM, 6.8% [95% CI, 6.7%-6.8%] vs PM, 5.1% [95% CI, 5.0%-5.2%]). Conclusions and Relevance: In this study, survival disparities associated with marital status were attributable to early diagnosis in breast, colorectal, and endometrial cancers as well as melanoma and to treatment-related variables in lung, pancreatic, and prostate cancers. The findings also suggest that marriage may play a greater protective role in the cancer-specific survival of men than of women.

Pd-Senphos Catalyzed trans-Selective Cyanoboration of 1,3-Enynes.

The first trans-selective cyanoboration reaction of an alkyne, specifically a 1,3-enyne, is described. The reported palladium-catalyzed cyanoboration of 1,3-enynes is site-, regio-, and diastereoselective, and is uniquely enabled by the 1,4-azaborine-based Senphos ligand structure. Tetra-substituted alkenyl nitriles are obtained providing useful boron-dienenitrile building blocks that can be further functionalized. The utility of our method has been demonstrated with the synthesis of Satigrel, an anti-platelet aggregating agent.

Core-Shell Structuring of Pure Metallic Aerogels towards Highly Efficient Platinum Utilization for the Oxygen Reduction Reaction.

The development of core-shell structures remains a fundamental challenge for pure metallic aerogels. Here we report the synthesis of Pdx Au-Pt core-shell aerogels composed of an ultrathin Pt shell and a composition-tunable Pdx Au alloy core. The universality of this strategy ensures the extension of core compositions to Pd transition-metal alloys. The core-shell aerogels exhibited largely improved Pt utilization efficiencies for the oxygen reduction reaction and their activities show a volcano-type relationship as a function of the lattice parameter of the core substrate. The maximum mass and specific activities are 5.25 A mgPt-1 and 2.53 mA cm-2 , which are 18.7 and 4.1 times higher than those of Pt/C, respectively, demonstrating the superiority of the core-shell metallic aerogels. The proposed core-based activity descriptor provides a new possible strategy for the design of future core-shell electrocatalysts.

Racial disparities in pancreatic neuroendocrine tumors survival: a SEER study.

Pancreatic neuroendocrine tumor (pancreatic NETs), is an important cause of cancer-related death worldwide. No study has rigorously explored the impact of ethnicity on pancreatic NETs. We aimed to demonstrate the relationship between ethnicity and the survival of patients with pancreatic NETs. We used the SEER database to identify patients with pancreatic NETs from 2004 to 2013. Kaplan-Meier methods and Cox proportional hazard models were used to evaluate the impact of race on survival in pancreatic NETs patients. A total of 3850 patients were included: 3357 Non-Blacks, 493 Blacks. We stratified races as "Black" and "White/Other." Blacks were more likely to be diagnosed with later stages of tumors (P = 0.021). As for the treatment, the access to surgery seemed to be more limited in Blacks than non-Black patients (P = 0.012). Compared with non-Black patients, Black patients have worse overall survival (OS) (HR = 1.17, 95% CI: 1.00-1.37, P = 0.046) and pancreatic neuroendocrine tumors specific survival (PNSS) (HR = 1.22, 95% CI: 1.01-1.48, P = 0.044). Multivariate Cox analysis identified that disease extension at the time of diagnosis and surgical status contributed to the ethnical survival disparity. Black patients whose stages at diagnosis were localized had significantly worse OS (HR = 2.09, 95% CI: 1.18-3.71, P = 0.011) and PNSS (HR = 3.79, 95% CI: 1.62-8.82, P = 0.002). As for the patients who did not receive surgery, Blacks also have a worse OS (HR = 1.18, 95% CI: 1.00-1.41, P = 0.045). The Black patients had both worse OS and PNSS compared to non-Black patients. The restricted utilization of surgery, and the advanced disease extension at the time of diagnosis are the possible contributors to poorer survival of Blacks with pancreatic NETs.

Marital status is an independent prognostic factor for pancreatic neuroendocrine tumors patients: An analysis of the Surveillance, Epidemiology, and End Results (SEER) database.

BACKGROUND AND OBJECTIVES: Marital status's prognostic impact on pancreatic neuroendocrine tumors (PNET) has not been rigorously studied. We aimed to explore the relationship between marital status and outcomes of PNET. METHODS: We retrospectively investigated 2060 PNET cases between 2004 and 2010 from Surveillance, Epidemiology, and End Results (SEER) database. Variables were compared by Chi2 test, t-test as appropriate. Kaplan-Meier methods and COX proportional hazard models were used to ascertain independent prognostic factors. RESULTS: Married patients had better 5-year overall survival (OS) (53.37% vs. 42.27%, P<0.001) and 5-year pancreatic neuroendocrine tumor specific survival (PNSS) (67.76% vs. 59.82%, P=0.001) comparing with unmarried patients. Multivariate analysis revealed marital status is an independent prognostic factor, with married patients showing better OS (HR=0.74; 95% CI: 0.65-0.84; P<0.001) and PNSS (HR=0.78; 95% CI: 0.66-0.92; P=0.004). Subgroup analysis suggested marital status plays a more important role in the PNET patients with distant stage rather than regional or localized disease. CONCLUSIONS: Marital status is an independent prognostic factor for survival in PNET patients. Poor prognosis in unmarried patients may be associated with a delayed diagnosis with advanced tumor stage, psychosocial and socioeconomic factors. Further studies are needed.

Site-Selective and Stereoselective trans-Hydroboration of 1,3-Enynes Catalyzed by 1,4-Azaborine-Based Phosphine-Pd Complex.

A concise synthesis of monobenzofused 1,4-azaborine phosphine ligands (Senphos) is described. These Senphos ligands uniquely support Pd-catalyzed trans-selective hydroboration of terminal and internal 1,3-enynes to furnish corresponding dienylboronates in high efficiency and diastereoselectivity. X-ray structural analysis of the Senphos-Pd(0) complex reveals a κ2-P-η2-BC coordination mode, and this isolated complex has been shown to serve as a competent catalyst for the trans-hydroboration reaction. This work demonstrates that the expanded chemical space provided by the BN/CC isosterism approach translates into the functional space in the context of stereoselective catalytic transformations.

A Modular Synthetic Approach to Monocyclic 1,4-Azaborines.

A simple and general method for the synthesis of a wide range of monocyclic 1,4-azaborines, including the first examples containing B heteroatoms is described. Post-heterocycle-formation olefin isomerization was employed as a key strategy. This new synthetic method provides fundamental insight into the resonance stabilization and photophysical properties of 1,4-azaborines.