Early failure is still a poor prognostic factor in patients with relapsed or refractory large B-cell lymphoma in the era of CAR T-cell therapy.

Patients with refractory or relapsed (R/R) large B-cell lymphoma (LBCL) refractory to first-line chemotherapy or with early relapse have poor outcomes. While chimeric antigen receptor (CAR) T-cell therapy has impressive efficacy after two or more lines of chemotherapy, it's still uncertain if these outcomes remain consistent in the context of third-line CAR T-cell therapy. We conducted a retrospective study of 107 R/R LBCL patients. Patients with relapse 12 months or more after their first-line chemoimmunotherapy (late failure: n = 25) had significantly longer overall survival (OS) than patients with refractory disease or relapse within 12 months (early failure: n = 82) (median OS: not achieved vs. 18.4 months; P < 0.001). Among patients who proceeded to autologous hematopoietic stem-cell transplantation (auto-HSCT), those with late failure had significantly longer event-free survival (EFS) than those with early failure (median EFS: 26.9 vs. 3.1 months; P = 0.012). However, no significant difference in EFS was detected among patients who underwent CAR T-cell therapy (median EFS: not reached vs. 11.8; P = 0.091). Cox regression with restricted cubic spline demonstrated that timing of relapse had significant impact on EFS in patients with auto-HSCT but not in patients with CAR T-cell therapy. Of patients who were scheduled for CAR T-cell therapy, those with late failure were significantly more likely to receive CAR T-cell therapy than those with early failure (90% vs. 57%; P = 0.008). In conclusion, patients with early failure still experienced poor outcomes after the approval of third-line CAR T-cell therapy.

Photoinduced Platinum-Catalyzed Reductive Allylation of α-Diketones with Allylic Carbonates.

A unique process for the photoinduced platinum-catalyzed reductive allylation of α-diketones with allylic carbonates has been developed. This allylation reaction was found to proceed selectively at the more electron-deficient carbonyl group of the diketone to afford an α-keto homoallylic alcohol. Such products could be further derivatized by transformation of the remaining carbonyl group. A mechanistic investigation suggests that a ketyl radical generated in response to photoirradiation reacts with a (π-allyl)platinum complex to form a C-C bond.

Photocatalytic 1,2-Phosphorus-Migrative [3 + 2] Cycloaddition of Tri(t-butyl)phosphine with Terminal Alkynes.

Tri(t-butyl)phosphine and terminal alkynes undergo 1,2-phosphorus-migrative [3 + 2] cycloaddition in the presence of a proton source under photocatalytic conditions. The reaction exhibits broad functional group tolerance and affords substituted cyclic phosphonium salts, which are amenable to further derivatization by Wittig olefination. Theoretical studies suggest that the phosphorus 1,2-migration of a ß-phosphonioalkyl radical proceeds through a phosphine radical cation-alkene complex as a pseudointermediate, and the two fragments in the intermediate are bound to each other through multiple noncovalent interactions.

Antifreeze protein type III addition to freezing extender comprehensively improves post-thaw sperm properties in Okinawan native Agu pig.

Sperm cryopreservation often leads to physical cell damage through ice crystal formation. This study evaluates the improvements to freezing extender cryoprotective activity due to antifreeze protein (AFP) addition, which primarily acts on ice crystal formation, through investigating the post-thaw sperm properties of Okinawan native Agu pig. Six individual boar sperm samples were diluted with the freezing extender supplemented with 1 µg/mL of AFP I or AFP III and then subjected to cryopreservation. Treatment with AFP I during the freezing procedure had no improvement for any characteristics after thawing compared to untreated sperm. In contrast, the addition of AFP III to the freezing extender strongly increased sperm motility, mitochondria and cell membrane integrity, and the acrosomal proteolytic activity of frozen-thawed sperm in 5 of 6 individuals (P < 0.05). Furthermore, cryoinjury prevention by AFP III significantly enhanced sperm viability (by ATP content), and maintained DNA quality and in vitro sperm penetrability compared with AFP I treatment (P < 0.05). These findings demonstrate that AFP III addition to the freezing extender of boar sperm is more effective in maintaining sperm characteristics than the extender without AFP III or AFP I, despite individual differences in response.

Sonoluminescence intensity and ultrasonic cavitation temperature in organic solvents: Effects of generated radicals.

Ultrasonic cavitation in organic solvents remains poorly understood in contrast with aqueous systems, largely because of complexities related to solvent decomposition. In this study, we sonicated different types of organic solvents (i.e. linear alkanes, aliphatic alcohols, aromatic alcohols, and acetate esters) under argon saturation. The average temperature of the cavitation bubbles was estimated using the methyl radical recombination method. We also discuss the effects of the physical properties of the solvents, such as vapor pressure and viscosity, on the cavitation temperature. The average cavitation bubble temperature and sonoluminescence intensity were higher in organic solvents with lower vapor pressure; for aromatic alcohols, these values were particularly high. It was found that the specific high sonoluminescence intensities and average cavitation temperatures exhibited in aromatic alcohols are caused by the highly resonance-stable generated radicals. The results obtained in this study are very useful for acceleration of sonochemical reaction in organic solvents, which are indispensable for organic synthesis and material synthesis.

Nickel-Catalyzed Defluorophosphonylation of Aryl Fluorides.

A Ni-catalyzed cross-coupling reaction between aryl fluorides and dialkyl phosphonates [HP(O)(OR)2] (R = secondary alkyl groups) in the presence of potassium tert-butoxide as a base is reported. The reaction converted various aryl fluorides into the corresponding aryl phosphonates even when electron-donating substituents were present on the aromatic ring. The combined experimental and computational studies suggested Ni-K+ cooperative action of a Ni(0) complex chelated with a strongly electron-donating ion-bridged dimeric phosphite ligand system [P(OR)2O-K+]2 that facilitates turnover-limiting C-F bond oxidative addition of aryl fluorides.

Separation of Glycoproteins Based on Sugar Chains Using Novel Stationary Phases Modified with Poly(ethylene glycol)-Conjugated Boronic-Acid Derivatives.

Boronic acid (BA) reversibly complexes with the diol structure. BA derivatives separate glycoproteins based on the differences in the sugar chains. Separation typically occurs under basic conditions, which does not guarantee the structural stability of glycoproteins. Here, 5-boronopicolinic acid (BPA) is used to prepare silica-gel based columns with poly(ethylene glycol) (PEG) as a linker to suppress nonselective adsorption and poly(ethylene imine) (PEI) as a scaffold to increase the BPA moiety density. High-performance liquid chromatography (HPLC) using only aqueous buffer solutions without organic solvents demonstrates the selective retention ability of the BPA columns for glycoproteins. BPA interacts with the diols in the sugar chains but not the proteins. In an evaluation for N-glycans, the BPA columns show a higher retention ability toward high mannose type and a lower affinity to N-acetylneuraminic acid (Neu5Ac). Finally, a pair of glycoproteins, fetuin and asialofetuin, are selectively separated due to the presence of Neu5Ac on the nonreducing end.

Photoinduced Hydrophosphination of Terminal Alkynes with Tri(o-tolyl)phosphine: Synthesis of Alkenylphosphonium Salts.

Herein reported is a photoinduced hydrophosphination reaction of terminal alkynes with tri(o-tolyl)phosphine to form alkenylphosphonium salts. The reaction is more sustainable than conventional methods since it dispenses with the need for elaborated starting materials and precious transition metals. The o-methyl groups of tri(o-tolyl)phosphine play two important roles: (1) to guide the phosphorus radical to add onto the terminal sp carbon and (2) to donate a hydrogen atom onto the developing sp2 carbon radical intramolecularly.

Addition of l-carnitine to the freezing extender improves post-thaw sperm quality of Okinawan native Agu pig.

The objective of the present study was to establish whether the addition of l-carnitine (LC), which exhibits antioxidant activity, to the freezing extender improves the quality of cryopreserved Okinawan native Agu pig sperm. Ejaculated sperm frozen in an extender supplemented with 0, 1, 2.5, or 5 mM LC was thawed, and the integrities of mitochondria and the plasmalemma and other sperm characteristics were evaluated. The treatment with different concentrations of LC effectively improved sperm motility, mitochondrial and plasmalemmal integrities, and the proteolytic activity of acrosomal contents after freeze-thawing (P < 0.05). The proportion of post-thaw sperm possessing intact mitochondria and plasmalemma and higher proteolytic activity of acrosomal contents was markedly higher among sperm frozen in the presence of 2.5 mM LC than among sperm frozen in the extender without LC (P < 0.05). Furthermore, although the addition of LC to the freezing extender had no effect on disturbance of DNA damage and caspase activity, sperm treated with 2.5 mM LC during freezing exhibited significantly higher penetrability into matured oocytes in vitro than untreated sperm. Collectively, these results indicate that the addition of LC to the freezing extender effectively improved the post-thaw quality of Agu pig sperm by preventing mitochondrial dysfunction caused by oxidative stress during cryopreservation.

Photoinduced Copper-Catalyzed Asymmetric Acylation of Allylic Phosphates with Acylsilanes.

We report a visible-light-induced copper-catalyzed highly enantioselective umpolung allylic acylation reaction with acylsilanes as acyl anion equivalents. Triplet-quenching experiments and DFT calculations supported our reaction design, which is based on copper-to-acyl metal-to-ligand charge transfer (MLCT) photoexcitation that generates a charge-separated triplet state as a highly reactive intermediate. According to the calculations, the allylic phosphate substrate in the excited state undergoes novel molecular activation into an allylic radical weakly bound to the copper complex. The allyl radical fragment undergoes copper-mediated regio- and stereocontrolled coupling with the acyl group under the influence of the chiral N-heterocyclic carbene ligand.

Photoinduced Reaction of Triarylphosphines with Alkenes Forming Fused Tricyclic Phosphonium Salts.

Herein reported is a photoinduced reaction of triarylphosphines with alkenes in the presence of carbonic acid. A drastic structural change occurs to produce fused tricyclic phosphonium salts having a phosphatricyclo[4.3.0.02.9]nonene core structure. The reaction was marked by dearomatizing transannulation of the phenyl ring, 1,2-migration of the phosphorus atom, and incorporation of an alkene. The highly endergonic process is promoted by cooperation of visible light with a photocatalyst under mild reaction conditions.

Photoinduced Dearomatizing Three-Component Coupling of Arylphosphines, Alkenes, and Water.

A unique photoinduced reaction that couples a triarylphosphine, an alkene, and water to produce 2-(cyclohexa-2,5-dienyl)ethylphosphine oxide is reported herein. The alkene inserts into a C(aryl)-P bond of the arylphosphine, the aryl ring is dearomatized into the cyclohexadienyl ring, and the phosphorus is oxidized. The three components are all readily available, and their intermolecular coupling significantly increases molecular complexity. The products formed are applicable to the Wittig olefination.

Separation of saccharides using fullerene-bonded silica monolithic columns via π interactions in liquid chromatography.

We report on a potential method to separate sugars by using the specific interaction between fullerenes and saccharides in liquid chromatography (LC). Aromatic rings with high electron density are believed to interact strongly with saccharides due to CH-π and/or OH-π interactions. In this study, the fullerene-bonded columns were used to separate saccharides by LC under aqueous conditions. As a result, 2-aminobenzamide-labeled glucose homopolymer (Glcs) was effectively separated by both C60 and C70 columns in the range of Glc-1 to Glc-20 and high blood glucose level being retained in greater quantity. Furthermore, similar separations were identified by LC-mass spectrometry with non-labeled glucose homopolymers. Theoretical study based on molecular dynamics and DFT calculation demonstrated that a supramolecular complex of saccharide-fullerene was formed through CH-π and/or OH-π interactions, and that the interactions between saccharide and fullerene increase with the increase units of the saccharide. Additionally, the C60 column retained disaccharides containing maltose, trehalose, and sucrose. In this case, it was assumed that the retention rates were determined by the difference of the dipole moment in each saccharide. These results suggest that the dipole-induced dipole interaction was dominant, and that maltose-with the higher dipole moment-was more strongly retained compared to other disaccharides having lower dipole moment.

Dehydrative Allylation of α C(sp3)-H Bonds of Alkylamines with Allylic Alcohols.

Herein reported is a dehydrative coupling reaction of alkyl amines with allylic alcohols promoted by co-operation of photoredox and palladium catalysts. A range of homoallylic amines are efficiently synthesized. A mechanistic study suggests that an in situ generated carboxylic acid activates an allylic alcohol to facilitate its oxidative addition onto palladium.

C1 Oxidation/C2 Reduction Isomerization of Unprotected Aldoses Induced by Light/Ketone.

Unprotected aldoses in water undergo an isomerization reaction via a radical pathway when irradiated with light in the presence of water-soluble benzophenone. Whereas its anomeric carbon (C1) is oxidized to a carboxy group, the hydroxy group on the C2 carbon is replaced by hydrogen. The generated 2-deoxy lactones are readily reduced to the corresponding 2-deoxy aldoses, which are often contained in bioactive compounds.

Carboxylation of Benzylic and Aliphatic C-H Bonds with CO2 Induced by Light/Ketone/Nickel.

A photoinduced carboxylation reaction of benzylic and aliphatic C-H bonds with CO2 is developed. Toluene derivatives capture gaseous CO2 at the benzylic position to produce phenylacetic acid derivatives when irradiated with UV light in the presence of an aromatic ketone, a nickel complex, and potassium tert-butoxide. Cyclohexane reacts with CO2 to furnish cyclohexanecarboxylic acid under analogous reaction conditions. The present photoinduced carboxylation reaction provides a direct access from readily available hydrocarbons to the corresponding carboxylic acids with one carbon extension.

Synthesis of Tofisopam by Way of Photoinduced CO2 Fixation.

Herein reported is a unique synthetic route of Tofisopam, an anxiolytic drug containing a 2,3-benzodiazepine core structure. 3,4-Dimethoxypropylbenzene and 3,4-dimethoxybenzoic acid, which are both of plant origin, and CO2 constitute its carbon skeleton. These three renewable substances are united by two C-C bond forming reactions, i.e., a Friedel-Crafts acylation reaction and a photoinduced carboxylation reaction to construct the major carbon framework. Finally, a methyl group is introduced by a Kumada-type cross-coupling reaction to furnish Tofisopam. Various analogs of Tofisopam are readily synthesized by introducing other substituents than a methyl group at the last C-C bond forming step.

Light/Palladium-Promoted Benzylic C-H Acylation Using a Benzoyl Group as the Photo-Directing Group.

2-Methylphenyl ketones undergo site-selective acylation at the benzylic position when treated with acid anhydride under UV irradiation in the presence of a palladium catalyst. The benzoyl carbonyl group serves as the photo-directing group so that the ortho benzylic C-H bond is activated site-selectively.

Overexpressing human GPR109A leads to pronounced reduction in plasma triglyceride levels in BAC transgenic rats.

BACKGROUND AND AIMS: Nicotinic acid administration causes plasma non-esterified fatty acid (NEFA) reduction and plasma lipid changes, including reduced triglyceride levels. GPR109A, which is expressed mainly in adipose tissue and has anti-lipolytic activity, was reported to be a molecular target for nicotinic acid. However, recent clinical reports have shown that most GPR109A agonists failed to induce clinically meaningful plasma lipid changes. In addition, a recent study has shown that the TG lowering effect of nicotinic acid was not diminished in Gpr109a deficient mice, which is different from the original finding. Therefore, whether GPR109A activation can lead to plasma lipid changes is unclear. METHODS: We created a bacterial artificial chromosome (BAC) transgenic rat expressing human GPR109A (Tg rat) and examined the in vivo role of GPR109A. RESULTS: Under fasted conditions, plasma NEFA and triglyceride levels in Tg rats were lower than those in non-Tg rats. In this condition, a positive correlation between plasma NEFA and triglyceride or ß-hydroxybutyrate levels was observed. Furthermore, insulin levels in Tg rats were lower than those in non-Tg rats only when a reduction in NEFAs was observed, which is a phenomenon also reported for nicotinic acid. Interestingly, body weight gain in Tg rats was significantly lower than in non-Tg rats. CONCLUSIONS: These results suggest that GPR109A signaling leads to a reduction in triglyceride and insulin levels, and that the triglyceride-lowering effect of nicotinic acid is at least partially mediated by GPR109A signaling.