CuH-Catalyzed Regio- and Enantioselective Formal Hydroformylation of Vinyl Arenes.

A highly enantioselective formal hydroformylation of vinyl arenes enabled by copper hydride (CuH) catalysis is reported. Key to the success of the method was the use of the mild Lewis acid zinc triflate to promote the formation of oxocarbenium electrophiles through the activation of diethoxymethyl acetate. Using the newly developed protocol, a broad range of vinyl arene substrates underwent efficient hydroacetalization reactions to provide access to highly enantioenriched α-aryl acetal products in good yields with exclusively branched regioselectivity. The acetal products could be converted to the corresponding aldehydes, alcohols, and amines with full preservation of the enantiomeric purity. Density functional theory studies support that the key C-C bond-forming event between the alkyl copper intermediate and the oxocarbenium electrophile takes place with inversion of configuration of the Cu-C bond in a backside SE2-type mechanism.

NAPE-PLD regulates specific baseline affective behaviors but is dispensable for inflammatory hyperalgesia.

N-acyl-ethanolamine (NAEs) serve as key endogenous lipid mediators as revealed by manipulation of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for metabolizing NAEs. Preclinical studies focused on FAAH or NAE receptors indicate an important role for NAE signaling in nociception and affective behaviors. However, there is limited information on the role of NAE biosynthesis in these same behavioral paradigms. Biosynthesis of NAEs has been attributed largely to the enzyme N-acylphosphatidylethanolamine Phospholipase D (NAPE-PLD), one of three pathways capable of producing these bioactive lipids in the brain. In this report, we demonstrate that Nape-pld knockout (KO) mice displayed reduced sucrose preference and consumption, but other baseline anxiety-like or depression-like behaviors were unaltered. Additionally, we observed sex-dependent responses in thermal nociception and other baseline measures in wildtype (WT) mice that were absent in Nape-pld KO mice. In the Complete Freund's Adjuvant (CFA) model of inflammatory arthritis, WT mice exhibited sex-dependent changes in paw edema that were lost in Nape-pld KO mice. However, there was no effect of Nape-pld deletion on arthritic pain-like behaviors (grip force deficit and tactile allodynia) in either sex, indicating that while NAPE-PLD may alter local inflammation, it does not contribute to pain-like behaviors associated with inflammatory arthritis. Collectively, these findings indicate that chronic and systemic NAPE-PLD inactivation will likely be well-tolerated, warranting further pharmacological evaluation of this target in other disease indications.

Association between single nucleotide polymorphism of DNA damage repair related genes and radiosensitivity in healthy individuals.

Radiosensitivity in humans can influence radiation-induced normal tissue toxicity. As radiosensitivity has a genetic predisposition, we aimed to investigate the possible association between four single nucleotide polymorphism (SNP) sites and the radiosensitivity in healthy people. We genotyped four selected SNPs: TRIP12 (rs13018957), UIMC1 (rs1700490) and POLN (rs2022302), and analyzed the association between SNP and the radiosensitivity in healthy people. We distinguished radiosensitivity by chromosome aberration analysis in healthy individuals. Healthy donors were classified into three groups based on chromosomal aberrations: resistant, normal and sensitive. Using the normal group as a reference, the genotypes CT and CC of rs13018957 (CT: OR = 26.13; CC: OR = 15.97), AA of rs1700490 (OR = 32.22) and AG of rs2022302 (OR = 13.98) were risk factors for radiosensitivity. The outcomes of the present study suggest that four SNPs are associated with radiosensitivity. This study lends insights to the underlying mechanisms of radiosensitivity and improves our ability to identify radiosensitive individuals.

Stereoselective Synthesis of Trisubstituted Alkenes via Copper Hydride-Catalyzed Alkyne Hydroalkylation.

Alkenes are ubiquitous in organic chemistry, yet many classes of alkenes remain challenging to access by current synthetic methodology. Herein, we report a copper hydride-catalyzed approach for the synthesis of Z-configured trisubstituted alkenes with high stereo- and regioselectivity via alkyne hydroalkylation. A DTBM-dppf-supported Cu catalyst was found to be optimal, providing a substantial increase in product yield compared to reactions conducted with dppf as the ligand. DFT calculations show that the DTBM substitution leads to the acceleration of alkyne hydrocupration through combined ground and transition state effects related to preventing catalyst dimerization and enhancing catalyst-substrate dispersion interactions, respectively. Alkyne hydroalkylation was successfully demonstrated with methyl and larger alkyl tosylate electrophiles to produce a variety of (hetero)aryl-substituted alkenes in moderate to high yields with complete selectivity for the Z stereochemically configured products. In the formation of the key C-C bond, computational studies revealed a direct SN2 pathway for alkylation of the vinylcopper intermediate with in situ-formed alkyl iodides.

Testing electron-phonon coupling for the superconductivity in kagome metal CsV3Sb5.

In crystalline materials, electron-phonon coupling (EPC) is a ubiquitous many-body interaction that drives conventional Bardeen-Cooper-Schrieffer superconductivity. Recently, in a new kagome metal CsV3Sb5, superconductivity that possibly intertwines with time-reversal and spatial symmetry-breaking orders is observed. Density functional theory calculations predicted weak EPC strength, λ, supporting an unconventional pairing mechanism in CsV3Sb5. However, experimental determination of λ is still missing, hindering a microscopic understanding of the intertwined ground state of CsV3Sb5. Here, using 7-eV laser-based angle-resolved photoemission spectroscopy and Eliashberg function analysis, we determine an intermediate λ=0.45-0.6 at T = 6 K for both Sb 5p and V 3d electronic bands, which can support a conventional superconducting transition temperature on the same magnitude of experimental value in CsV3Sb5. Remarkably, the EPC on the V 3d-band enhances to λ~0.75 as the superconducting transition temperature elevated to 4.4 K in Cs(V0.93Nb0.07)3Sb5. Our results provide an important clue to understand the pairing mechanism in the kagome superconductor CsV3Sb5.

Human factors engineering of BCI: an evaluation for satisfaction of BCI based on motor imagery.

Existing brain-computer interface (BCI) research has made great progress in improving the accuracy and information transfer rate (ITR) of BCI systems. However, the practicability of BCI is still difficult to achieve. One of the important reasons for this difficulty is that human factors are not fully considered in the research and development of BCI. As a result, BCI systems have not yet reached users' expectations. In this study, we investigate a BCI system of motor imagery for lower limb synchronous rehabilitation as an example. From the perspective of human factors engineering of BCI, a comprehensive evaluation method of BCI system development is proposed based on the concept of human-centered design and evaluation. Subjects' satisfaction ratings for BCI sensors, visual analog scale (VAS), subjects' satisfaction rating of the BCI system, and the mental workload rating for subjects manipulating the BCI system, as well as interview/follow-up comprehensive evaluation of motor imagery of BCI (MI-BCI) system satisfaction were used. The methods and concepts proposed in this study provide useful insights for the design of personalized MI-BCI. We expect that the human factors engineering of BCI could be applied to the design and satisfaction evaluation of MI-BCI, so as to promote the practical application of this kind of BCI.

circRNF10 Regulates Tumorigenic Properties and Natural Killer Cell-Mediated Cytotoxicity against Breast Cancer through the miR-934/PTEN/PI3k-Akt Axis.

Circular RNA (circRNA), a type of non-coding RNA, has received a great deal of attention with regard to the initiation and progression of tumors. However, the molecular mechanism and function of circRNAs in breast cancer (BC) remain unclear. In the current study, we discovered that hsa_circ_0028899 (also called circRNF10) was significantly reduced in BC tissues, and a higher level of circRNF10 was markedly related to a favorable prognosis. The results of CCK8, colony formation, Transwell, ELISA, and NK cell-mediated cytotoxicity assays indicated that increased circRNF10 expression could significantly repress the proliferation, invasion, and migration of BC cells and enhance the killing efficiency of NK cells against BC cells. According to these biological functions, the possible role and molecular mechanism of circRNF10 in BC cells were further investigated. We used bioinformatics prediction tools to predict circRNF10-bound miRNAs, which were verified by many experimental studies, including FISH, luciferase reporter assays, RIP, and Western blots. These data suggest that circRNF10 serves as a molecular sponge for miR-934 to further regulate PTEN expression and PI3k/Akt/MICA signaling in vitro and tumor growth in vivo. Altogether, these findings reveal that circRNF10 functions as a novel anti-oncogene in BC via sponging miR-934 and suppressing the PI3K/Akt/MICA pathway.

Dual-Gradient Unified Chromatography: A New Paradigm for Versatility in Simultaneous Multicomponent Analysis.

Generality in analytical chemistry can be manifested in impactful platforms that can streamline modern organic synthesis and biopharmaceutical processes. We herein introduce a hybrid separation technique named Dual-Gradient Unified Chromatography (DGUC), which is built upon an automated dynamic modulation of CO2 , organic modifier, and water blends with various buffers. This concept enables simultaneous multicomponent analysis of both small and large molecules across a wide polarity range in single experimental runs. After a careful investigation of its fundamental aspects, a DGUC-DAD-MS screening workflow that combines multiple orthogonal column and mobile phase choices across a far-reaching universal elution profile is also reported. The power of this framework is demonstrated with new analytical applications guiding academic and industrial laboratories in the development of new (bio)pharmaceutical targets (e.g. synthetic intermediates, nucleosides, cyclic and linear peptides, proteins, antibody drug conjugates).

Copper Hydride-Catalyzed Enantioselective Olefin Hydromethylation.

The enantioselective installation of a methyl group onto a small molecule can result in the significant modification of its biological properties. While hydroalkylation of olefins represents an attractive approach to introduce alkyl substituents, asymmetric hydromethylation protocols are often hampered by the incompatibility of highly reactive methylating reagents and a lack of general applicability. Herein, we report an asymmetric olefin hydromethylation protocol enabled by CuH catalysis. This approach leverages methyl tosylate as a methyl source compatible with the reducing base-containing reaction environment, while a catalytic amount of iodide ion transforms the methyl tosylate in situ into the active reactant, methyl iodide, to promote the hydromethylation. This method tolerates a wide range of functional groups, heterocycles, and pharmaceutically relevant frameworks. Density functional theory studies suggest that after the stereoselective hydrocupration, the methylation step is stereoretentive, taking place through an SN2-type oxidative addition mechanism with methyl iodide followed by a reductive elimination.

Enantioselective Hydrocarbamoylation of Alkenes.

The asymmetric hydroaminocarbonylation of olefins represents a straightforward approach for the synthesis of enantioenriched amides, but is hampered by the necessity to employ CO gas, often at elevated pressures. We herein describe, as an alternative, an enantioselective hydrocarbamoylation of alkenes leveraging dual copper hydride and palladium catalysis to enable the use of readily available carbamoyl chlorides as a practical carbamoylating reagent. The protocol is applicable to various types of olefins, including alkenyl arenes, terminal alkenes, and 1,1-disubstituted alkenes. Substrates containing a diverse range of functional groups as well as heterocyclic substructures undergo functionalization to provide α- and ß-chiral amides in good yields and with excellent enantioselectivities.

Confronting the Challenging Asymmetric Carbonyl 1,2-Addition Using Vinyl Heteroarene Pronucleophiles: Ligand-Controlled Regiodivergent Processes through a Dearomatized Allyl-Cu Species.

The selective reductive coupling of vinyl heteroarenes with aldehydes and ketones represents a versatile approach for the rapid construction of enantiomerically enriched secondary and tertiary alcohols, respectively. Herein, we demonstrate a CuH-catalyzed regiodivergent coupling of vinyl heteroarenes with carbonyl-containing electrophiles, in which the selectivity is controlled by the ancillary ligand. This approach leverages an in situ generated benzyl- or dearomatized allyl-Cu intermediate, yielding either the dearomatized or exocyclic addition products, respectively. The method exhibits excellent regio-, diastereo-, and enantioselectivity and tolerates a range of common functional groups and heterocycles. The dearomative pathway allows direct access to a variety of functionalized saturated heterocyclic structures. The reaction mechanism was probed using a combination of experimental and computational approach. Density functional theory studies suggest that the ligand-controlled regioselectivity results from the C-H/π interaction and steric repulsion in transition states, leading to the major and minor regioisomers, respectively. Hydrocupration of vinyl heteroarene pronucleophile is the enantiodetermining step, whereas the diastereoselectivity is enforced by steric interactions between the benzylic or allyl-Cu intermediate and carbonyl-containing substrates in a six-membered cyclic transition state.

O-Heterocycle Synthesis via Intramolecular C-H Alkoxylation Catalyzed by Iron Acetylacetonate.

Intramolecular alkoxylation of C-H bonds can rapidly introduce structural and functional group complexities into seemingly simple or inert precursors. The transformation is particularly important due to the ubiquitous presence of tetrahydrofuran (THF) motifs as fundamental building blocks in a wide range of pharmaceuticals, agrochemicals, and natural products. Despite the various synthetic methodologies known for generating functionalized THFs, most show limited functional group tolerance and lack demonstration for the preparation of spiro or fused bi- and tricyclic ether units prevalent in molecules for pharmacological purposes. Herein we report an intramolecular C-H alkoxylation to furnish oxacycles from easily prepared α-diazo-ß-ketoesters using commercially available iron acetylacetonate (Fe(acac)2) as a catalyst. The reaction is proposed to proceed through the formation of a vinylic carboradical arising from N2 extrusion, which mediates a proximal H-atom abstraction followed by a rapid C-O bond forming radical recombination step. The radical mechanism is probed using an isotopic labeling study (vinyl C-D incorporation), ring opening of a radical clock substrate, and Hammett analysis and is further corroborated by density functional theory (DFT) calculations. Heightened reactivity is observed for electron-rich C-H bonds (tertiary, ethereal), while greater catalyst loadings or elevated reaction temperatures are required to fully convert substrates with benzylic, secondary, and primary C-H bonds. The transformation is highly functional group tolerant and operates under mild reaction conditions to provide rapid access to complex structures such as spiro and fused bi-/tricyclic O-heterocycles from readily available precursors.

Enantioselective C-H Amination Catalyzed by Nickel Iminyl Complexes Supported by Anionic Bisoxazoline (BOX) Ligands.

The trityl-substituted bisoxazoline (TrHBOX) was prepared as a chiral analogue to a previously reported nickel dipyrrin system capable of ring-closing amination catalysis. Ligand metalation with divalent NiI2(py)4 followed by potassium graphite reduction afforded the monovalent (TrHBOX)Ni(py) (4). Slow addition of 1.4 equiv of a benzene solution of 1-adamantylazide to 4 generated the tetrazido (TrHBOX)Ni(κ2-N4Ad2) (5) and terminal iminyl adduct (TrHBOX)Ni(NAd) (6). Investigation of 6 via single-crystal X-ray crystallography, NMR and EPR spectroscopies, and computations revealed a Ni(II)-iminyl radical formulation, similar to its dipyrrinato congener. Complex 4 exhibits enantioselective intramolecular C-H bond amination to afford N-heterocyclic products from 4-aryl-2-methyl-2-azidopentanes. Catalytic C-H amination occurs under mild conditions (5 mol % catalyst, 60 °C) and provides pyrrolidine products in decent yield (29%-87%) with moderate ee (up to 73%). Substrates with a 3,5-dialkyl substitution on the 4-aryl position maximized the observed enantioselectivity. Kinetic studies to probe the reaction mechanism were conducted using 1H and 19F NMR spectroscopies. A small, intermolecular kinetic isotope effect (1.35 ± 0.03) suggests an H-atom abstraction step with an asymmetric transition state while the reaction rate is measured to be first order in catalyst and zeroth order in substrate concentrations. Enantiospecific deuterium labeling studies show that the enantioselectivity is dictated by both the H-atom abstraction and radical recombination steps due to the comparable rate between radical rotation and C-N bond formation. Furthermore, the competing elements of the two-step reaction where H-removal from the pro-R configuration is preferred while the preferential radical capture occurs with the Si face of the carboradical likely lead to the diminished ee observed, as corroborated by theoretical calculations. Based on these enantio-determining steps, catalytic enantioselective synthesis of 2,5-bis-tertiary pyrrolidines is demonstrated with good yield (50-78%) and moderate ee (up to 79%).

Revealing redox isomerism in trichromium imides by anomalous diffraction.

In polynuclear biological active sites, multiple electrons are needed for turnover, and the distribution of these electrons among the metal sites is affected by the structure of the active site. However, the study of the interplay between structure and redox distribution is difficult not only in biological systems but also in synthetic polynuclear clusters since most redox changes produce only one thermodynamically stable product. Here, the unusual chemistry of a sterically hindered trichromium complex allowed us to probe the relationship between structural and redox isomerism. Two structurally isomeric trichromium imides were isolated: asymmetric terminal imide (tbsL)Cr3(NDipp) and symmetric, µ3-bridging imide (tbsL)Cr3(µ3-NBn) ((tbsL)6- = (1,3,5-C6H9(NC6H4-o-NSi t BuMe2)3)6-). Along with the homovalent isocyanide adduct (tbsL)Cr3(CNBn) and the bisimide (tbsL)Cr3(µ3-NPh)(NPh), both imide isomers were examined by multiple-wavelength anomalous diffraction (MAD) to determine the redox load distribution by the free refinement of atomic scattering factors. Despite their compositional similarities, the bridging imide shows uniform oxidation of all three Cr sites while the terminal imide shows oxidation at only two Cr sites. Further oxidation from the bridging imide to the bisimide is only borne at the Cr site bound to the second, terminal imido fragment. Thus, depending on the structural motifs present in each [Cr3] complex, MAD revealed complete localization of oxidation, partial localization, and complete delocalization, all supported by the same hexadentate ligand scaffold.

Efficient and selective alkene hydrosilation promoted by weak, double Si-H activation at an iron center.

Cationic iron complexes [Cp*(iPr2MeP)FeH2SiHR]+, generated and characterized in solution, are very efficient catalysts for the hydrosilation of terminal alkenes and internal alkynes by primary silanes at low catalyst loading (0.1 mol%) and ambient temperature. These reactions yield only the corresponding secondary silane product, even with SiH4 as the substrate. Mechanistic experiments and DFT calculations indicate that the high rate of hydrosilation is associated with an inherently low barrier for dissociative silane exchange (product release).

Efficient C-H Amination Catalysis Using Nickel-Dipyrrin Complexes.

A dipyrrin-supported nickel catalyst (AdFL)Ni(py) (AdFL: 1,9-di(1-adamantyl)-5-perfluorophenyldipyrrin; py: pyridine) displays productive intramolecular C-H bond amination to afford N-heterocyclic products using aliphatic azide substrates. The catalytic amination conditions are mild, requiring 0.1-2 mol% catalyst loading and operational at room temperature. The scope of C-H bond substrates was explored and benzylic, tertiary, secondary, and primary C-H bonds are successfully aminated. The amination chemoselectivity was examined using substrates featuring multiple activatable C-H bonds. Uniformly, the catalyst showcases high chemoselectivity favoring C-H bonds with lower bond dissociation energy as well as a wide range of functional group tolerance (e.g., ethers, halides, thioetheres, esters, etc.). Sequential cyclization of substrates with ester groups could be achieved, providing facile preparation of an indolizidine framework commonly found in a variety of alkaloids. The amination cyclization reaction mechanism was examined employing nuclear magnetic resonance (NMR) spectroscopy to determine the reaction kinetic profile. A large, primary intermolecular kinetic isotope effect (KIE = 31.9 ± 1.0) suggests H-atom abstraction (HAA) is the rate-determining step, indicative of H-atom tunneling being operative. The reaction rate has first order dependence in the catalyst and zeroth order in substrate, consistent with the resting state of the catalyst as the corresponding nickel iminyl radical. The presence of the nickel iminyl was determined by multinuclear NMR spectroscopy observed during catalysis. The activation parameters (ΔH‡ = 13.4 ± 0.5 kcal/mol; ΔS‡= -24.3 ± 1.7 cal/mol·K) were measured using Eyring analysis, implying a highly ordered transition state during the HAA step. The proposed mechanism of rapid iminyl formation, rate-determining HAA, and subsequent radical recombination was corroborated by intramolecular isotope labeling experiments and theoretical calculations.

CRISPR/Cas9-deaminase enables robust base editing in Rhodobacter sphaeroides 2.4.1.

BACKGROUND: CRISPR/Cas9 systems have been repurposed as canonical genome editing tools in a variety of species, but no application for the model strain Rhodobacter sphaeroides 2.4.1 was unveiled. RESULTS: Here we showed two kinds of programmable base editing systems, cytosine base editors (CBEs) and adenine base editors (ABEs), generated by fusing endonuclease Cas9 variant to cytosine deaminase PmCDA1 or heterodimer adenine deaminase TadA-TadA*, respectively. Using CBEs, we were able to obtain C-to-T mutation of single and double targets following the first induction step, with the efficiency of up to 97% and 43%; while the second induction step was needed in the case of triple target, with the screening rate of 47%. Using ABEs, we were only able to gain A-to-G mutation of single target after the second induction step, with the screening rate of 30%. Additionally, we performed a knockout analysis to identify the genes responsible for coenzyme Q10 biosynthesis and found that ubiF, ubiA, ubiG, and ubiX to be the most crucial ones. CONCLUSIONS: Together, CBEs and ABEs serve as alternative methods for genetic manipulation in Rhodobacter sphaeroides and will shed light on the fundamental research of other bacteria that are hard to be directly edited by Cas9-sgRNA.

Synthesis and electronic structure studies of a Cr-imido redox series.

The effect of metal identity, d-electron count, and coordination geometry on the electronic structure of a metal-ligand multiple bond (MLMB) is an area of active exploration. Although high oxidation state Cr imidos have been extensively studied, very few reports on low-valent Cr imidos or the interconversion of redox isomers exist. Herein, we report the synthesis and characterization of a family of dipyrrinato Cr imido complexes in oxidation states ranging from CrIII to CrV, showcasing the influence of the weak-field dipyrromethene scaffold on the electronic structure and coordination geometries of these Cr imides.

Synthesis, characterization and C-H amination reactivity of nickel iminyl complexes.

Metalation of the deprotonated dipyrrin (AdFL)Li with NiCl2(py)2 afforded the divalent Ni product (AdFL)NiCl(py)2 (1) (AdFL: 1,9-di(1-adamantyl)-5-perfluorophenyldipyrrin; py: pyridine). To generate a reactive synthon on which to explore oxidative group transfer, we used potassium graphite to reduce 1, affording the monovalent Ni synthon (AdFL)Ni(py) (2) and concomitant production of a stoichiometric equivalent of KCl and pyridine. Slow addition of mesityl- or 1-adamantylazide in benzene to 2 afforded the oxidized Ni complexes (AdFL)Ni(NMes) (3) and (AdFL)Ni(NAd) (4), respectively. Both 3 and 4 were characterized by multinuclear NMR, EPR, magnetometry, single-crystal X-ray crystallography, theoretical calculations, and X-ray absorption spectroscopies to provide a detailed electronic structure picture of the nitrenoid adducts. X-ray absorption near edge spectroscopy (XANES) on the Ni reveals higher energy Ni 1s → 3d transitions (3: 8333.2 eV; 4: 8333.4 eV) than NiI or unambiguous NiII analogues. N K-edge X-ray absorption spectroscopy performed on 3 and 4 reveals a common low-energy absorption present only for 3 and 4 (395.4 eV) that was assigned via TDDFT as an N 1s promotion into a predominantly N-localized, singly occupied orbital, akin to metal-supported iminyl complexes reported for iron. On the continuum of imido (i.e., NR2-) to iminyl (i.e., 2NR-) formulations, the complexes are best described as NiII-bound iminyl species given the N K-edge and TDDFT results. Given the open-shell configuration (S = 1/2) of the iminyl adducts, we then examined their propensity to undergo nitrenoid-group transfer to organic substrates. The adamantyl complex 4 readily consumes 1,4-cyclohexadiene (CHD) via H-atom abstraction to afford the amide (AdFL)Ni(NHAd) (5), whereas no reaction was observed upon treatment of the mesityl variant 3 with excess amount of CHD over 3 hours. Toluene can be functionalized by 4 at room temperature, exclusively affording the N-1-adamantyl-benzylidene (6). Slow addition of the organoazide substrate (4-azidobutyl)benzene (7) with 2 exclusively forms 4-phenylbutanenitrile (8) as opposed to an intramolecular cyclized pyrrolidine, resulting from facile ß-H elimination outcompeting H-atom abstraction from the benzylic position, followed by rapid H2-elimination from the intermediate Ni hydride ketimide intermediate.

Efficacy of Thalidomide in Preventing Delayed Nausea and Vomiting Induced by Highly Emetogenic Chemotherapy: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase III Trial (CLOG1302 study).

Purpose We examined the efficacy and safety of thalidomide (THD) for the prevention of delayed nausea and vomiting in patients who received highly emetogenic chemotherapy (HEC). Patients and Methods In a randomized, double-blind, active-controlled, phase III trial, chemotherapy-naive patients with cancer who were scheduled to receive HEC that contained cisplatin or cyclophosphamide-doxorubicin/epirubincin ≥ 50 mg/m2 regimens were randomly assigned to a THD group (100 mg twice daily on days 1 to 5) or placebo group, both with palonosetron (0.25 mg on day 1) and dexamethasone (12 mg on day 1; 8 mg on days 2 to 4). Primary end point was complete response to vomiting-no emesis or use of rescue medication-in the delayed phase (25 to 120 h). Nausea and anorexia on days 1 to 5 were evaluated by the 4-point Likert scale (0, no symptoms; 3, severe). Quality of life was assessed by the European Organization for Research and Treatment of Cancer QLQ-C30 version 3 questionnaire on days -1 and 6. Results Of 656 patients, 638 were evaluable: 317 in the THD group and 321 in the control group. Compared with placebo, delayed and overall (0 to 120 h) complete response rates to vomiting were significantly higher with THD: 76.9% versus 61.7% ( P < .001) and 66.1% versus 53.3% ( P = .001), respectively. Rates of no nausea were also higher in the THD group (delayed: 47.3% v 33.3%; P < .001; overall: 41% v 29.6%; P = .003), and mean scores of anorexia were lower overall (0.44 ± 0.717 v 0.64 ± 0.844; P = .003). Adverse effects were mild to moderate. The THD group had increased sedation, dizziness, constipation, and dry mouth, but experienced better quality of life after chemotherapy. Conclusion Thalidomide combined with palonosetron and dexamethasone significantly improved HEC-induced delayed nausea and vomiting prevention in chemotherapy-naive patients.