NCCN Guidelines® Insights: Colorectal Cancer Screening, Version 1.2024.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age at which to initiate screening in average-risk individuals and those with increased risk based on personal history of childhood, adolescent, and young adult cancer.

Triflic Acid-Catalyzed Dehydrative Amination of 2-Arylethanols with Weak N-Nucleophiles in Hexafluoroisopropanol.

The catalytic deoxyamination of readily available 2-arylethanols offers an appealing, simple, and straightforward means of accessing ß-(hetero)arylethylamines of biological interest. Yet, it currently represents a great challenge to synthetic chemistry. In most cases, the alcohol has to be either pre-activated in situ or converted into a reactive carbonyl intermediate, limiting the substrate scope for some methods. Examples of direct dehydrative amination of 2-arylethanols are still scarce. Here, we describe a catalytic protocol based on the synergy of triflic acid and hexafluoroisopropanol, which enables the direct and stereospecific amination of a broad array of 2-arylethanols, and does not require any pre-activation of the alcohol. This approach yields high value-added products incorporating sulfonamide, amide, urea, and aniline functionalities. In addition, this approach was applied to the sulfidation of 2-arylethanols. Mechanistic experiments and DFT computations indicate the formation of phenonium ions as key intermediates in the reaction.

Measuring Kinetics under Vibrational Strong Coupling: Testing for a Change in the Nucleophilicity of Water and Alcohols.

Vibrational Strong Coupling (VSC) has been reported to change the rate of organic reactions. However, a lack of convenient and reliable methods to measure reaction kinetics under VSC makes it challenging to obtain mechanistic insight into its influence, hindering progress in the field. Here, we use recently developed fixed-width optical cavities to obtain large kinetic datasets under VSC with small errors (±1-5 %) in an operationally simple manner using UV/Vis spectroscopy. The setup is used to test whether VSC changes a fundamental kinetic property of polar reactions, nucleophilicity, for water and alcohols, species commonly used in VSC-modified chemistry. We determined the rate constants for nucleophilic capture with a library of benzhydrilium ions as reference electrophiles with and without strong coupling of the nucleophile's key vibrations. For all investigated combinations of electrophiles and nucleophiles, only minor changes in the observed rate constants of the reactions were observed independently of the coupled bands. These results indicate that VSC does not substantially alter the nucleophilicity of water and alcohols, suggesting that polar reactions are modified through other, presently unknown mechanisms. Fixed-width cavities allow for convenient and reproducible UV/Vis kinetics, facilitating mechanistic studies of VSC-modified chemistry.

Pyridinium-Derived Mesoionic N-Heterocyclic Olefins (py-mNHOs).

Mesoionic polarization allows access to electron-rich olefins that have found application as organocatalysts, ligands, or nucleophiles. Herein, we report the synthesis and characterization of a series of 3-methylpyridinium-derived mesoionic olefins (py-mNHOs). We used a DFT-supported design concept, which showed that the introduction of aryl groups in the 1-, 2-, 4-, and 6-positions of the heterocyclic core allowed the kinetic stabilization of the novel mesoionic compounds. Tolman electronic parameters indicate that py-mNHOs are remarkably strong σ-donor ligands toward transition metals and main group Lewis acids. Additionally, they are among the strongest nucleophiles on the Mayr reactivity scale. In reactions of py-mNHOs with electron-poor π-systems, a gradual transition from the formation of zwitterionic adducts via stepwise to concerted 1,3-dipolar cycloadditions was observed experimentally and analyzed by quantum-chemical calculations.

Unraveling C-Selective Ring-Opening of Phosphiranes with Carboxylic Acids and Other Nucleophiles: A Mechanistically-Driven Approach.

Phosphiranes are weak Lewis bases reacting with only a limited number of electrophiles to produce the corresponding phosphiranium ions. These salts are recognized for their propensity to undergo reactions with oxygen pronucleophiles at the phosphorus site, leading to the formation of phosphine oxide adducts. Building on a thorough mechanistic understanding, we have developed an unprecedented approach that enables the selective reaction of carboxylic acids, and other nucleophiles, at the carbon site of phosphiranes. This method involves the photochemical generation of highly reactive carbenes, which react with 1-mesitylphosphirane to yield ylides. The latter undergoes a stepwise reaction with carboxylic acids, resulting in the production of the desired phosphines. In addition to DFT calculations, we have successfully isolated and fully characterized the key intermediates involved in the reaction.

Metal/ADP Complexes Promote Phosphorylation of Ribonucleotides.

Under enzyme catalysis, adenosine triphosphate (ATP) transfers a phosphoryl group to canonical ribonucleotide diphosphates (NDPs) to form ribonucleotide triphosphates (NTPs), the direct biosynthetic precursors to RNA. However, it remains unclear whether the phosphorylation of NDPs could have occurred in water before enzymes existed and why an adenosine derivative, rather than another canonical NTP, typically performs this function. Here, we show that adenosine diphosphate (ADP) in the presence of Fe3+ or Al3+ promotes phosphoryl transfer from acetyl phosphate to all canonical NDPs to produce their corresponding NTP in water at room temperature and in the absence of enzymes. No other NDPs were found to promote phosphorylation, giving insight into why adenosine derivatives specifically became used for this purpose in biology. The metal-ADP complexes also promote phosphoryl transfer to ribonucleoside monophosphates (NMPs) to form a mixture of the corresponding NDPs and NTPs, albeit less efficiently. This work represents a rare example in which a single nucleotide carries out a function critical to biology without enzymes. ADP-metal complexes may have played an important role in nucleotide phosphorylation in prebiotic chemistry.

One-Bond-Nucleophilicity and -Electrophilicity Parameters: An Efficient Ordering System for 1,3-Dipolar Cycloadditions.

Diazoalkanes are ambiphilic 1,3-dipoles that undergo fast Huisgen cycloadditions with both electron-rich and electron-poor dipolarophiles but react slowly with alkenes of low polarity. Frontier molecular orbital (FMO) theory considering the 3-center-4-electron π-system of the propargyl fragment of diazoalkanes is commonly applied to rationalize these reactivity trends. However, we recently found that a change in the mechanism from cycloadditions to azo couplings takes place due to the existence of a previously overlooked lower-lying unoccupied molecular orbital. We now propose an alternative approach to analyze 1,3-dipolar cycloaddition reactions, which relies on the linear free energy relationship lg k2(20 °C) = sN(N + E) (eq 1) with two solvent-dependent parameters (N, sN) to characterize nucleophiles and one parameter (E) for electrophiles. Rate constants for the cycloadditions of diazoalkanes with dipolarophiles were measured and compared with those calculated for the formation of zwitterions by eq 1. The difference between experimental and predicted Gibbs energies of activation is interpreted as the energy of concert, i.e., the stabilization of the transition states by the concerted formation of two new bonds. By linking the plot of lg k2 vs N for nucleophilic dipolarophiles with that of lg k2 vs E for electrophilic dipolarophiles, one obtains V-shaped plots which provide absolute rate constants for the stepwise reactions on the borderlines. These plots furthermore predict relative reactivities of dipolarophiles in concerted, highly asynchronous cycloadditions more precisely than the classical correlations of rate constants with FMO energies or ionization potentials. DFT calculations using the SMD solvent model confirm these interpretations.

Metal-Pyridoxal Cooperativity in Nonenzymatic Transamination.

Coenzymes are involved in ≥30% of enzymatic reactions and likely predate enzymes, going back to prebiotic chemistry. However, they are considered poor organocatalysts, and thus their pre-enzymatic function remains unclear. Since metal ions are known to catalyze metabolic reactions in the absence of enzymes, here we explore the influence of metal ions on coenzyme catalysis under conditions relevant to the origin of life (20-75 °C, pH 5-7.5). Specifically, Fe or Al, the two most abundant metals in the Earth's crust, were found to exhibit substantial cooperative effects in transamination reactions catalyzed by pyridoxal (PL), a coenzyme scaffold used by roughly 4% of all enzymes. At 75 °C and 7.5 mol % loading of PL/metal ion, Fe3+-PL was found to be 90-fold faster at catalyzing transamination than PL alone and 174-fold faster than Fe3+ alone, whereas Al3+-PL was 85-fold faster than PL alone and 38-fold faster than Al3+ alone. Under milder conditions, reactions catalyzed by Al3+-PL were >1000 times faster than those catalyzed by PL alone. Pyridoxal phosphate (PLP) exhibited similar behavior to PL. Experimental and theoretical mechanistic studies indicate that the rate-determining step in the PL-metal-catalyzed transamination is different from metal-free and biological PL-based catalysis. Metal coordination to PL lowers the pKa of the PL-metal complex by several units and slows the hydrolysis of imine intermediates by up to 259-fold. Coenzymes, specifically pyridoxal derivatives, could have exhibited useful catalytic function even before enzymes.

Dietary fat in relation to all-cause mortality and cancer progression and death among people with metastatic colorectal cancer: Data from CALGB 80405 (Alliance)/SWOG 80405.

Data on diet and survival among people with metastatic colorectal cancer are limited. We examined dietary fat in relation to all-cause mortality and cancer progression or death among 1149 people in the Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group (SWOG) 80405 trial who completed a food frequency questionnaire at initiation of treatment for advanced or metastatic colorectal cancer. We examined saturated, monounsaturated, total and specific types (n-3, long-chain n-3 and n-6) of polyunsaturated fat, animal and vegetable fats. We hypothesized higher vegetable fat intake would be associated with lower risk of all-cause mortality and cancer progression. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Over median follow-up of 6.1 years (interquartile range [IQR]: 5.3, 7.2 y), we observed 974 deaths and 1077 events of progression or death. Participants had a median age of 59 y; 41% were female and 86% identified as White. Moderate or higher vegetable fat was associated with lower risk of mortality and cancer progression or death (HRs comparing second, third and fourth to first quartile for all-cause mortality: 0.74 [0.62, 0.90]; 0.75 [0.61, 0.91]; 0.79 [0.63, 1.00]; P trend: .12; for cancer progression or death: 0.74 [0.62, 0.89]; 0.78 [0.64, 0.95]; 0.71 [0.57, 0.88]; P trend: .01). No other fat type was associated with all-cause mortality and cancer progression or death. Moderate or higher vegetable fat intake may be associated with lower risk of cancer progression or death among people with metastatic colorectal cancer.

Pain Medicine Milestones 2.0: a step into the future.

OBJECTIVE: To describe the process of revising the Pain Medicine Milestones 1.0 and implementing changes into the Pain Medicine Milestones 2.0 along with implications for pain medicine trainees. BACKGROUND: Competency-based medical education has been implemented in graduate medical education, including pain medicine. Milestones 1.0, introduced by the Accreditation Council for Graduate Medical Education (ACGME), has been used to assess learners in six competencies and respective sub-competencies. Recognizing areas for improvement in Milestones 1.0, the ACGME initiated the process of Milestones 2.0 and a working group was created to execute this task for pain medicine. The working group discussed revisions; consensus was sought when changes were introduced. Final milestones were agreed upon and made available for public comment prior to publication. RESULTS: Redundant sub-competencies were either merged or eliminated, reducing the number of sub-competencies. A maximum of three rows representing skill, knowledge, behavior and attitude were included for each sub-competency. Harmonized Milestones, aligning with other specialties in a predetermined ACGME framework, were adopted and modified to meet the needs of pain medicine. A supplemental guide was developed to assist educators in implementation of Milestones 2.0 and assessment of trainees. CONCLUSIONS: The intent of the Milestones 2.0 was to create an improved tool that is comprehensive, easier to utilize, and of increased value for pain medicine training programs. It is expected that implementation of Milestones 2.0 will streamline pain medicine trainee assessments by educators and prepare trainees for the future practice of pain medicine while serving to be the foundation of an iterative process to match the evolution of the specialty.

Marital Status, Living Arrangement, and Cancer Recurrence and Survival in Patients with Stage III Colon Cancer: Findings from CALGB 89803 (Alliance).

BACKGROUND: Limited and conflicting findings have been reported regarding the association between social support and colorectal cancer (CRC) outcomes. We sought to assess the influences of marital status and living arrangement on survival outcomes among patients with stage III colon cancer. PATIENTS AND METHODS: We conducted a secondary analysis of 1082 patients with stage III colon cancer prospectively followed in the CALGB 89803 randomized adjuvant chemotherapy trial. Marital status and living arrangement were both self-reported at the time of enrollment as, respectively, married, divorced, separated, widowed, or never-married, and living alone, with a spouse or partner, with other family, in a nursing home, or other. RESULTS: Over a median follow-up of 7.6 years, divorced/separated/widowed patients experienced worse outcomes relative to those married regarding disease free-survival (DFS) (hazards ratio (HR), 1.44 (95% CI, 1.14-1.81); P =.002), recurrence-free survival (RFS) (HR, 1.35 (95% CI, 1.05-1.73); P = .02), and overall survival (OS) (HR, 1.40 (95% CI, 1.08-1.82); P =.01); outcomes were not significantly different for never-married patients. Compared to patients living with a spouse/partner, those living with other family experienced a DFS of 1.47 (95% CI, 1.02-2.11; P = .04), RFS of 1.34 (95% CI, 0.91-1.98; P = .14), and OS of 1.50 (95% CI, 1.00-2.25; P =.05); patients living alone did not experience significantly different outcomes. CONCLUSION: Among patients with stage III colon cancer who received uniform treatment and follow-up within a nationwide randomized clinical trial, being divorced/separated/widowed and living with other family were significantly associated with greater colon cancer mortality. Interventions enhancing social support services may be clinically relevant for this patient population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00003835.

Quantification of the Electrophilicities of Diazoalkanes: Kinetics and Mechanism of Azo Couplings with Enamines and Sulfonium Ylides.

Kinetics and mechanism of the reactions of methyl diazoacetate, dimethyl diazomalonate, 4-nitrophenyldiazomethane, and diphenyldiazomethane with sulfonium ylides and enamines were investigated by UV-Vis and NMR spectroscopy. Ordinary alkenes undergo 1,3-dipolar cycloadditions with these diazo compounds. In contrast, sulfonium ylides and enamines attack at the terminal nitrogen of the diazo alkanes to give zwitterions, which undergo various subsequent reactions. As only one new bond is formed in the rate-determining step of these reactions, the correlation lg k2 (20 °C)=sN (N+E) could be used to determine the one-bond electrophilicities E of the diazo compounds from the measured second-order rate constants and the known reactivity indices N and sN of the sulfonium ylides and enamines. The resulting electrophilicity parameters (-21

Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue.

5-Aza-2'-deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2'-deoxycytidine (dC) to 5-methyl-dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM-13 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti-proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off-target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug.

Quantification of the hydride donor abilities of NADH, NADPH, and BH3CN- in water.

The nucleophilic reactivities of the hydride donors NADH, NADPH, and BH3CN- in water were quantified using kinetic measurements with benzhydrylium ions as reference electrophiles. All three hydride donors were found to possess almost identical nucleophilic reactivities, providing a potential explanation for why they are involved in similar transformations in biochemistry and organic synthesis, respectively.

Quantifying Reductive Amination in Nonenzymatic Amino Acid Synthesis.

Amino acid biosynthesis initiates with the reductive amination of α-ketoglutarate with ammonia to produce glutamate. However, the other α-keto acids derived from the glyoxylate and Krebs cycles are converted into amino acids by transamination, rather than by reductive amination. Why is only one amino acid synthesized by reductive amination and not the others? To explore this question, we quantified the inherent reactivities of keto acids in nonenzymatic reduction and reductive amination by using BH3 CN- as a model nucleophile. Biological α-keto acids were found to show pronounced nonenzymatic reactivity differences for the formation of amino acids (α-ketoglutarate

An Overlooked Pathway in 1,3-Dipolar Cycloadditions of Diazoalkanes with Enamines.

Methyl diazoacetate reacts with 1-(N-pyrrolidino)cycloalkenes to give products of 1,3-dipolar cycloadditions and azo couplings. The kinetics and mechanisms of these reactions were investigated by NMR spectroscopy and DFT calculations. Orthogonal π-systems in the 1,3-dipoles of the propargyl-allenyl type allow for two separate reaction pathways for the (3+2)-cycloadditions. The commonly considered concerted pathway is rationalized by the interaction of the enamine HOMO with LUMO+1, the lowest unoccupied orbital of the heteropropargyl anion fragment of methyl diazoacetate. We show that HOMO/LUMO(π*N=N ) interactions between enamines and methyl diazoacetate open a previously unrecognized reaction path for stepwise cycloadditions through zwitterionic intermediates with barriers approximately 40 kJ mol-1 lower in energy in CHCl3 (DFT calculations) than for the concerted path.

Mechanistic Insight into Metal Ion-Catalyzed Transamination.

Several classes of biological reactions that are mediated by an enzyme and a co-factor can occur, to a slower extent, not only without the enzyme but even without the co-factor, under catalysis by metal ions. This observation has led to the proposal that metabolic pathways progressively evolved from using inorganic catalysts to using organocatalysts of increasing complexity. Transamination, the biological process by which ammonia is transferred between amino acids and α-keto acids, has a mechanism that has been well studied under enzyme/co-factor catalysis and under co-factor catalysis, but the metal ion-catalyzed variant was generally studied mostly at high temperatures (70-100 °C), and the details of its mechanism remained unclear. Here, we investigate which metal ions catalyze transamination under conditions relevant to biology (pH 7, 20-50 °C) and study the mechanism in detail. Cu2+, Ni2+, Co2+, and V5+ were identified as the most active metal ions under these constraints. Kinetic, stereochemical, and computational studies illuminate the mechanism of the reaction. Cu2+ and Co2+ are found to predominantly speed up the reaction by stabilizing a key imine intermediate. V5+ is found to accelerate the reaction by increasing the acidity of the bound imine. Ni2+ is found to do both to a limited extent. These results show that direct metal ion-catalyzed amino group transfer is highly favored even in the absence of co-factors or protein catalysts under biologically compatible reaction conditions.

Lewis Acidic Boranes, Lewis Bases, and Equilibrium Constants: A Reliable Scaffold for a Quantitative Lewis Acidity/Basicity Scale.

A quantitative Lewis acidity/basicity scale toward boron-centered Lewis acids has been developed based on a set of 90 experimental equilibrium constants for the reactions of triarylboranes with various O-, N-, S-, and P-centered Lewis bases in dichloromethane at 20 °C. Analysis with the linear free energy relationship log KB =LAB +LBB allows equilibrium constants, KB , to be calculated for any type of borane/Lewis base combination through the sum of two descriptors, one for Lewis acidity (LAB ) and one for Lewis basicity (LBB ). The resulting Lewis acidity/basicity scale is independent of fixed reference acids/bases and valid for various types of trivalent boron-centered Lewis acids. It is demonstrated that the newly developed Lewis acidity/basicity scale is easily extendable through linear relationships with quantum-chemically calculated or common physical-organic descriptors and known thermodynamic data (ΔH BF 3 ). Furthermore, this experimental platform can be utilized for the rational development of borane-catalyzed reactions.

Macrolactonization Reactions Driven by a Pentafluorobenzoyl Group*.

Macrolactones constitute a privileged class of natural and synthetic products with a broad range of applications in the fine chemicals and pharmaceutical industry. Despite all the progress made towards their synthesis, notably from seco-acids, a macrolactonization promoter system that is effective, selective, flexible, readily available, and, insofar as possible, compatible with manifold functional groups is still lacking. Herein, we describe a strategy that relies on the formation of a mixed anhydride incorporating a pentafluorophenyl group which, due to its high electronic activation enables a convenient access to macrolactones, macrodiolides and esters with a broad versatility. Kinetic studies and DFT computations were performed to rationalize the reactivity of the pentafluorophenyl group in macrolactonization reactions.

From Carbodiimides to Carbon Dioxide: Quantification of the Electrophilic Reactivities of Heteroallenes.

Kinetics of the reactions of isocyanates, isothiocyanates, carbodiimides, carbon disulfide, and carbon dioxide with carbanions or enamines (reference nucleophiles) have been measured photometrically in acetonitrile or DMSO solution at 20 °C. The resulting second-order rate constants and the previously published reactivity parameters N and sN of the reference nucleophiles were substituted into the correlation log k2(20 °C) = sN(N + E) to determine the electrophilicity parameters of the heteroallenes: TsNCO (E = -7.69) ≫ PhNCO (E = -15.38) > CS2 (E = -17.70) ≈ PhNCS (E = -18.15) > PhNCNPh (E = -20.14) ≫ CyNCNCy (E ≈ -30). An approximate value could be derived for CO2 (-16 < E < - 11). Quantum chemical calculations were performed at the IEFPCM(DMSO)/B3LYP-D3/6-311+G(d,p) level of theory and compared with experimental Gibbs activation energies. The distortion-interaction model was used to rationalize the different reactivities of O- and S-substituted heteroallenes. Eventually it is demonstrated that the electrophilicity parameters determined in this work can be used as ordering principle for literature-known reactions of heteroallenes.