Soluble Methane Monooxygenase.

Aerobic life is possible because the molecular structure of oxygen (O2) makes direct reaction with most organic materials at ambient temperatures an exceptionally slow process. Of course, these reactions are inherently very favorable, and they occur rapidly with the release of a great deal of energy at high temperature. Nature has been able to tap this sequestered reservoir of energy with great spatial and temporal selectivity at ambient temperatures through the evolution of oxidase and oxygenase enzymes. One mechanism used by these enzymes for O2 activation has been studied in detail for the soluble form of the enzyme methane monooxygenase. These studies have revealed the step-by-step process of O2 activation and insertion into the ultimately stable C-H bond of methane. Additionally, an elegant regulatory mechanism has been defined that enlists size selection and quantum tunneling to allow methane oxidation to occur specifically in the presence of more easily oxidized substrates.

Porous Organic Nanotubes: Chemistry of One-Dimensional Space.

ConspectusOne-dimensional organic nanotubes feature unique properties, such as confined chemical environments and transport channels, which are highly desirable for many applications. Advances in synthetic methods have enabled the creation of different types of organic nanotubes, including supramolecular, hydrogen-bonded, and carbon nanotube analogues. However, challenges associated with chemical and mechanical stability along with difficulties in controlling aspect ratios remain a significant bottleneck. The fascination with structured porous materials has paved the way for the emergence of reticular solids such as metal-organic frameworks (MOFs), covalent organic frameworks (COFs), and organic cages. Reticular materials with tubular morphology promise architectural stability with the additional benefit of permeant porosity. Despite this, the current synthetic approaches to these reticular nanotubes focus more on structural design resulting in less reliable morphological uniformity. This Account, highlights the design motivation behind various classes of organic nanotubes, emphasizing their porous interior space. We explore the strategic assembly of organic nanotubes based on their bonding characteristics, from weak supramolecular to robust covalent interactions. Special attention is given to reticular nanotubes, which have gained prominence over the past two decades due to their distinctive micro and mesoporous structures. We examine the synergy of covalent and noncovalent interactions in constructing assembly of these nanotube structures.This Account furnishes a comprehensive overview of our efforts and advancements in developing porous covalent organic nanotubes (CONTs). We describe a general synthetic approach for creating robust imine-linked nanotubes based on the reticular chemistry principles. The use of spatially oriented tetratopic triptycene-based amine and linear ditopic aldehyde building blocks facilitates one-dimensional nanotube growth. The interplay between directional covalent bonds and solvophobic interactions is crucial for forming uniform, well-defined, and high aspect ratio nanotubes. The nanotubes derive their permeant porosity and thermal and chemical stability from their covalent architecture. We also highlight the adaptability of our synthetic methodology to guide the transformation of one-dimensional nanotubes to toroidal superstructures and two-dimensional thin fabrics. Such morphological transformation can be directed by tuning the reaction time or incorporating additional intermolecular interactions to control the intertwining behavior of individual nanotubes. The cohesion of covalent and noncovalent interactions in the tubular nanostructures manifests superior viscoelastic mechanical properties in the assembled CONT fabrics. We establish a strong correlation between structural framework design and nanostructures by translating reticular synthesis to morphological space and gaining insights into the assembly processes. We anticipate that the present Account will lay the foundation for exploring new designs and chemistry of organic nanotubes for many application platforms.

Covalent Organic Frameworks for the Purification of Recombinant Enzymes and Heterogeneous Biocatalysis.

Recombinant enzymes have gained prominence due to their diverse functionalities and specificity and are often a greener alternative in biocatalysis. This context makes purifying recombinant enzymes from host cells and other impurities crucial. The primary goal is to isolate the pure enzyme of interest and ensure its stability under ambient conditions. Covalent organic frameworks (COFs), renowned for their well-ordered structure and permeability, offer a promising approach for purifying histidine-tagged (His-tagged) enzymes. Furthermore, immobilizing enzymes within COFs represents a growing field in heterogeneous biocatalysis. In this study, we have developed a flow-based technology utilizing a nickel-infused covalent organic framework (Ni-TpBpy COF) to combine two distinct processes: the purification of His-tagged enzymes and the immobilization of enzymes simultaneously. Our work primarily focuses on the purification of three His-tagged enzymes ß-glucosidase, cellobiohydrolase, and endoglucanase as well as two proteins with varying molecular weights, namely, green fluorescent protein (27 kDa) and BG Rho (88 kDa). We employed Ni-TpBpy as a column matrix to showcase the versatility of our system. Additionally, we successfully obtained a Ni-TpBpy COF immobilized with enzymes, which can serve as a heterogeneous catalyst for the hydrolysis of p-nitrophenyl-ß-d-glucopyranoside and carboxymethylcellulose. These immobilized enzymes demonstrated catalytic activity comparable to that of their free counterparts, with the added advantages of recyclability and enhanced stability under ambient conditions for an extended period, ranging from 60 to 90 days. This contrasts with the free enzymes, which do not maintain their activity as effectively over time.

Chimeric antigen receptor and bispecific T-cell engager therapies in multiple myeloma patients with prior allogeneic transplantation.

Chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR-T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo-HCT). Thirty-three MM patients with prior allo-HCT received CAR-T (n = 24) or BsAb (n = 9) therapy. CAR-T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR-T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR-T and 78% of BsAb recipients, while immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in three CAR-T patients. Infections of grade ≥3 were reported in 50% of CAR-T and 44% of BsAb recipients. No exacerbation of graft-versus-host disease occurred except in one BsAb recipient. CAR-T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo-HCT.

Thickness-Driven Synthesis and Applications of Covalent Organic Framework Nanosheets.

Covalent organic frameworks (COFs) are two-dimensional, crystalline porous framework materials with numerous scopes for tunability, such as porosity, functionality, stability and aspect ratio (thickness to length ratio). The manipulation of π-stacking in COFs results in truly 2D materials, namely covalent organic nanosheets (CONs), adds advantages in many applications. In this Minireview, we have discussed both top-down (COFs→CONs) and bottom-up (molecules→CONs) approaches with precise information on thickness and lateral growth. We have showcased the research progress on CONs in a few selected applications, such as batteries, catalysis, sensing and biomedical applications. This Minireview specifically highlights the reports where the authors compare the performance of CONs with COFs by demonstrating the impact of the thickness and lateral growth of the nanosheets. We have also provided the possible scope of exploration of CONs research in terms of inter-dimensional conversion, such as graphene to carbon nanotube and future technologies.

Enhancing the Crystallinity of Keto-enamine-Linked Covalent Organic Frameworks through an in situ Protection-Deprotection Strategy.

ß-Keto-enamine-linked 2D covalent organic frameworks (COFs) have emerged as highly robust materials, showing significant potential for practical applications. However, the exclusive reliance on 1,3,5-triformylphloroglucinol (Tp aldehyde) in the design of such COFs often results in the production of non-porous amorphous polymers when combined with certain amine building blocks. Attempts to adjust the crystallinity and porosity by a modulator approach are inefficient because Tp aldehyde readily forms stable ß-keto-enamine-linked monomers/oligomers with various aromatic amines through an irreversible keto-enol tautomerization process. Our research employed a unique protection-deprotection strategy to enhance the crystallinity and porosity of ß-keto-enamine-linked squaramide-based 2D COFs. Advanced solid-state NMR studies, including 1D 13 C CPMAS, 1 H fast MAS, 15 N CPMAS, 2D 13 C-1 H correlation, 1 H-1 H DQ-SQ, and 14 N-1 H HMQC NMR were used to establish the atomic-level connectivity within the resultant COFs. The TpOMe -Sqm COFs synthesized utilizing this strategy have a surface area of 487 m2 g-1 , significantly higher than similar COFs synthesized using Tp aldehyde. Furthermore, detailed time-dependent PXRD, solid-state 13 C CPMAS NMR, and theoretical DFT studies shed more light on the crystallization and linkage conversion processes in these 2D COFs. Ultimately, we applied this protection-deprotection method to construct novel keto-enamine-linked highly porous organic polymers with a surface area of 1018 m2 g-1 .

Covalent Organic Frameworks as Porous Pigments for Photocatalytic Metal-Free C-H Borylation.

Covalent organic frameworks (COFs) are highly promising as heterogeneous photocatalysts due to their tunable structures and optoelectronic properties. Though COFs have been used as heterogeneous photocatalysts, they have mainly been employed in water splitting, carbon dioxide reduction, and hydrogen evolution reactions. A few examples in organic synthesis using metal-anchored COF photocatalysts were reported. Herein, we report highly stable ß-keto-enamine-based COFs as photocatalysts for metal-free C-B bond formation reactions. Three different COFs have been availed for this purpose. Their photocatalysis performances have been monitored for 12 different substrates, like quinolines, pyridines, and pyrimidines. All the COFs showcase moderate-to-high yields (up to 96%) depending upon the substrate's molecular functionality. High crystallinity, a large surface area, a low band gap, and a suitable band position result in the highest catalytic activity of TpAzo COF. The thorough mechanistic investigation further highlights the crucial role of light-harvesting capacity, charge separation efficiency, and current density during catalysis. The light absorbance capacity of the COF plays a critical role during catalysis as yields are maximized near the COF's absorption maxima. The high photostability of the as-synthesized COFs offers their reusability for several (>5) catalytic cycles.

Proximity-Enabled Photochemical C-H Functionalization using a Covalent Organic Framework-Confined Fe2IV-µ-oxo Species in Water.

Water has been recognized as an excellent solvent for maneuvering both the catalytic activity and selectivity, especially in the case of heterogeneous catalysis. However, maintaining the active catalytic species in their higher oxidation states (IV/V) while retaining the catalytic activity and recyclability in water is an enormous challenge. Herein, we have developed a solution to this problem using covalent organic frameworks (COFs) to immobilize the (Et4N)2[FeIII(Cl)bTAML] molecules, taking advantage of the COF's morphology and surface charge. By using the visible light and [CoIII(NH3)5Cl]Cl2 as a sacrificial electron acceptor within the COF, we have successfully generated and stabilized the [(bTAML)FeIV-O-FeIV(bTAML)]- species in water. The COF backbone simultaneously acts as a porous host and a photosensitizer. This is the first time that the photochemically generated Fe2IV-µ-oxo radical cation species has demonstrated high catalytic activity with moderate to high yield for the selective oxidation of the unactivated C-H bonds, even in water. To enhance the catalytic activity and achieve good recyclability, we have developed a TpDPP COF film by transforming the TpDPP COF nanospheres. We have achieved the regio- and stereoselective functionalization of unactivated C-H bonds of alkanes and alkenes (3°:2° = 102:1 for adamantane with the COF film), which is improbable in homogeneous conditions. The film exhibits C-H bond oxidation with higher catalytic yield (32-98%) and a higher degree of selectivity (cis/trans = 74:1; 3°:2° = 100:1 for cis-decalin).

Bottom-Up Synthesis of Crystalline Covalent Organic Framework Nanosheets, Nanotubes, and Kippah Vesicles: An Odd-Even Effect Induction.

Few-layer organic nanosheets are becoming increasingly attractive as two-dimensional (2D) materials due to their precise atomic connectivity and tailor-made pores. However, most strategies for synthesizing nanosheets rely on surface-assisted methods or top-down exfoliation of stacked materials. A bottom-up approach with well-designed building blocks would be the convenient pathway to achieve the bulk-scale synthesis of 2D nanosheets with uniform size and crystallinity. Herein, we have synthesized crystalline covalent organic framework nanosheets (CONs) by reacting tetratopic thianthrene tetraaldehyde (THT) and aliphatic diamines. The bent geometry of thianthrene in THT retards the out-of-plane stacking, while the flexible diamines introduce dynamic characteristics into the framework, facilitating nanosheet formation. Successful isoreticulation with five diamines with two to six carbon chain lengths generalizes the design strategy. Microscopic imaging reveals that the odd and even diamine-based CONs transmute to different nanostructures, such as nanotubes and hollow spheres. The single-crystal X-ray diffraction structure of repeating units indicates that the odd-even linker units of diamines introduce irregular-regular curvature in the backbone, aiding such dimensionality conversion. Theoretical calculations shed more light on nanosheet stacking and rolling behavior with respect to the odd-even effects.

Selective Metal-Free CO2 Photoreduction in Water Using Porous Nanostructures with Internal Molecular Free Volume.

The conversion of CO2 to a sole carbonaceous product using photocatalysis is a sustainable solution for alleviating the increasing levels of CO2 emissions and reducing our dependence on nonrenewable resources such as fossil fuels. However, developing a photoactive, metal-free catalyst that is highly selective and efficient in the CO2 reduction reaction (CO2RR) without the need for sacrificial agents, cocatalysts, and photosensitizers is challenging. Furthermore, due to the poor solubility of CO2 in water and the kinetically and thermodynamically favored hydrogen evolution reaction (HER), designing a highly selective photocatalyst is challenging. Here, we propose a molecular engineering approach to design a photoactive polymer with high CO2 permeability and low water diffusivity, promoting the mass transfer of CO2 while suppressing HER. We have incorporated a contorted triptycene scaffold with "internal molecular free volume (IMFV)" to enhance gas permeability to the active site by creating molecular channels through the inefficient packing of polymer chains. Additionally, we introduced a pyrene moiety to promote visible-light harvesting capability and charge separation. By leveraging these qualities, the polymer exhibited a high CO generation rate of 77.8 µmol g-1 h-1, with a high selectivity of ∼98% and good recyclability. The importance of IMFV was highlighted by replacing the contorted triptycene unit with a planar scaffold, which led to a selectivity reversal favoring HER over CO2RR in water. In situ electron paramagnetic resonance (EPR), time-resolved photoluminescence spectroscopy (TRPL), and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) techniques, further supported by theoretical calculations, were employed to enlighten the mechanistic insight for metal-free CO2 reduction to exclusively CO in water.

Covalent Organic Framework Cladding on Peptide-Amphiphile-Based Biomimetic Catalysts.

Peptide-based biomimetic catalysts are promising materials for efficient catalytic activity in various biochemical transformations. However, their lack of operational stability and fragile nature in non-aqueous media limit their practical applications. In this study, we have developed a cladding technique to stabilize biomimetic catalysts within porous covalent organic framework (COF) scaffolds. This methodology allows for the homogeneous distribution of peptide nanotubes inside the COF (TpAzo and TpDPP) backbone, creating strong noncovalent interactions that prevent leaching. We synthesized two different peptide-amphiphiles, C10FFVK and C10FFVR, with lysine (K) and arginine (R) at the C-termini, respectively, which formed nanotubular morphologies. The C10FFVK peptide-amphiphile nanotubes exhibit enzyme-like behavior and efficiently catalyze C-C bond cleavage in a buffer medium (pH 7.5). We produced nanotubular structures of TpAzo-C10FFVK and TpDPP-C10FFVK through COF cladding by using interfacial crystallization (IC). The peptide nanotubes encased in the COF catalyze C-C bond cleavage in a buffer medium as well as in different organic solvents (such as acetonitrile, acetone, and dichloromethane). The TpAzo-C10FFVK catalyst, being heterogeneous, is easily recoverable, enabling the reaction to be performed for multiple cycles. Additionally, the synthesis of TpAzo-C10FFVK thin films facilitates catalysis in flow. As control, we synthesized another peptide-amphiphile, C10FFVR, which also forms tubular assemblies. By depositing TpAzo COF crystallites on C10FFVR nanotubes through IC, we produced TpAzo-C10FFVR nanotubular structures that expectedly did not show catalysis, suggesting the critical role of the lysines in the TpAzo-C10FFVK.

Covalent Organic Framework Thin-Film Photodetectors from Solution-Processable Porous Nanospheres.

The synthesis of homogeneous covalent organic framework (COF) thin films on a desired substrate with decent crystallinity, porosity, and uniform thickness has great potential for optoelectronic applications. We have used a solution-processable sphere transmutation process to synthesize 300 ± 20 nm uniform COF thin films on a 2 × 2 cm2 TiO2-coated fluorine-doped tin oxide (FTO) surface. This process controls the nucleation of COF crystallites and molecular morphology that helps the nanospheres to arrange periodically to form homogeneous COF thin films. We have synthesized four COF thin films (TpDPP, TpEtBt, TpTab, and TpTta) with different functional backbones. In a close agreement between the experiment and density functional theory, the TpEtBr COF film showed the lowest optical band gap (2.26 eV) and highest excited-state lifetime (8.52 ns) among all four COF films. Hence, the TpEtBr COF film can participate in efficient charge generation and separation. We constructed optoelectronic devices having a glass/FTO/TiO2/COF-film/Au architecture, which serves as a model system to study the optoelectronic charge transport properties of COF thin films under dark and illuminated conditions. Visible light with a calibrated intensity of 100 mW cm-2 was used for the excitation of COF thin films. All of the COF thin films exhibit significant photocurrent after illumination with visible light in comparison to the dark. Hence, all of the COF films behave as good photoactive substrates with minimal pinhole defects. The fabricated out-of-plane photodetector device based on the TpEtBr COF thin film exhibits high photocurrent density (2.65 ± 0.24 mA cm-2 at 0.5 V) and hole mobility (8.15 ± 0.64 ×10-3 cm2 V-1 S-1) compared to other as-synthesized films, indicating the best photoactive characteristics.

Nuclear Resonance Vibrational Spectroscopy Definition of Peroxy Intermediates in Catechol Dioxygenases: Factors that Determine Extra- versus Intradiol Cleavage.

The extradiol dioxygenases (EDOs) and intradiol dioxygenases (IDOs) are nonheme iron enzymes that catalyze the oxidative aromatic ring cleavage of catechol substrates, playing an essential role in the carbon cycle. The EDOs and IDOs utilize very different FeII and FeIII active sites to catalyze the regiospecificity in their catechol ring cleavage products. The factors governing this difference in cleavage have remained undefined. The EDO homoprotocatechuate 2,3-dioxygenase (HPCD) and IDO protocatechuate 3,4-dioxygenase (PCD) provide an opportunity to understand this selectivity, as key O2 intermediates have been trapped for both enzymes. Nuclear resonance vibrational spectroscopy (in conjunction with density functional theory calculations) is used to define the geometric and electronic structures of these intermediates as FeII-alkylhydroperoxo (HPCD) and FeIII-alkylperoxo (PCD) species. Critically, in both intermediates, the initial peroxo bond orientation is directed toward extradiol product formation. Reaction coordinate calculations were thus performed to evaluate both the extra- and intradiol O-O cleavage for the simple organic alkylhydroperoxo and for the FeII and FeIII metal catalyzed reactions. These results show the FeII-alkylhydroperoxo (EDO) intermediate undergoes facile extradiol O-O bond homolysis due to its extra e-, while for the FeIII-alkylperoxo (IDO) intermediate the extradiol cleavage involves a large barrier and would yield the incorrect extradiol product. This prompted our evaluation of a viable mechanism to rearrange the FeIII-alkylperoxo IDO intermediate for intradiol cleavage, revealing a key role in the rebinding of the displaced Tyr447 ligand in this rearrangement, driven by the proton delivery necessary for O-O bond cleavage.

Cytomegalovirus seropositivity is associated with improved responses to CD38 monoclonal antibody therapies in multiple myeloma: A single-centre retrospective study.

The CD38-targeting monoclonal antibodies (CD38 mAbs) are well-established therapies in multiple myeloma (MM), but responses to treatment are not always deep or durable. Natural killer (NK) cells deficient in Fc epsilon receptor gamma subunits, known as g-NK cells, are found in higher numbers among individuals exposed to cytomegalovirus (CMV) and are able to potentiate the efficacy of daratumumab in vivo. Here, we present a single-centre, retrospective analysis of 136 patients with MM with known CMV serostatus who received a regimen containing a CD38 mAb (93.4% daratumumab and 6.6% isatuximab). CMV seropositivity was associated with an increased overall response rate to treatment regimens containing a CD38 mAb (odds ratio 2.65, 95% confidence interval [CI] 1.17-6.02). However, CMV serostatus was associated with shorter time to treatment failure in a multivariate Cox model (7.8 vs. 8.8 months in the CMV-seropositive vs. CMV-seronegative groups respectively, log-rank p = 0.18, hazard ratio 1.98, 95% CI 1.25-3.12). Our data suggest that CMV seropositivity may predict better response to CD38 mAbs, although this did not correspond to longer time to treatment failure. Larger studies directly quantitating g-NK cells are required to fully understand their effect on CD38 mAb efficacy in MM.

Where the Sidewalk Ends: Parenting as a Trainee during COVID-19.

Physicians who are also parents have faced significant difficulties during the COVID-19 pandemic. However, most studies of the physician-parent workforce have focused on the experiences of attending physicians. In this commentary, we highlight the ways that trainee parents have uniquely experienced three major stressors during the pandemic: (1) childcare challenges, (2) scheduling difficulties, and (3) career uncertainties. We discuss potential solutions to mitigate these challenges for the future hematology/oncology workforce. As the pandemic continues, we hope that these steps can improve the ability of trainee parents to care both for their patients and their families.

Professional Challenges for United States Hematology/Oncology Trainees during COVID-19.

COVID-19 has been devastating for patients with cancer. In this commentary, we chronicle the pandemic's downstream impacts on United States hematology/oncology trainees in terms of professional development and career advancement. These include loss of access to clinical electives and protocol workshops, delays in research approval and execution, mentor shortages due to academic burnout, and obstacles with career transitions (most notably the post-fellowship job search). While certain silver linings from the pandemic have undoubtedly emerged, continued progress against COVID-19 will be essential to fully overcome the professional challenges it has created for the future hematology/oncology workforce.

Hypoxia-specific imaging in patients with lymphoma undergoing CAR-T therapy.

PURPOSE: Intratumoral hypoxia in non-Hodgkin's Lymphoma (NHL) may interfere with chimeric antigen receptor T-cell (CAR-T) function. We conducted a single-center pilot study (clinicaltrials.gov ID NCT04409314) of [18F]fluoroazomycin arabinoside, a hypoxia-specific radiotracer abbreviated as [18F]FAZA, to assess the feasibility of this positron emission tomography (PET) imaging modality in this population. METHODS: Patients with relapsed NHL being evaluated for CAR-T therapy received a one-time [18F]FAZA PET scan before pre-CAR-T lymphodepletion. A tumor to mediastinum (T/M) ratio of 1.2 or higher with regard to [18F]FAZA uptake was defined as positive for intratumoral hypoxia. We planned to enroll 30 patients with an interim futility analysis after 16 scans. RESULTS: Of 16 scanned patients, 3 had no evidence of disease by standard [18F]fluorodeoxyglucose PET imaging before CAR-T therapy. Six patients (38%) had any [18F]FAZA uptake above background. Using a T/M cutoff of 1.20, only one patient (a 68-year-old male with relapsed diffuse large B-cell lymphoma) demonstrated intratumoral hypoxia in an extranodal chest wall lesion (T/M 1.35). Interestingly, of all 16 scanned patients, he was the only patient with progressive disease within 1 month of CAR-T therapy. However, because of our low overall proportion of positive scans, our study was stopped for futility. CONCLUSIONS: Our pilot study identified low-level [18F]FAZA uptake in a small number of patients with NHL receiving CAR-T therapy. The only patient who met our pre-specified threshold for intratumoral hypoxia was also the only patient with early CAR-T failure. Future plans include exploration of [18F]FAZA in a more selected patient population.

Ferritin-Like Proteins: A Conserved Core for a Myriad of Enzyme Complexes.

Ferritin-like proteins share a common fold, a four α-helix bundle core, often coordinating a pair of metal ions. Although conserved, the ferritin fold permits a diverse set of reactions, and is central in a multitude of macromolecular enzyme complexes. Here, we emphasize this diversity through three members of the ferritin-like superfamily: the soluble methane monooxygenase, the class I ribonucleotide reductase and the aldehyde deformylating oxygenase. They all rely on dinuclear metal cofactors to catalyze different challenging oxygen-dependent reactions through the formation of multi-protein complexes. Recent studies using cryo-electron microscopy, serial femtosecond crystallography at an X-ray free electron laser source, or single-crystal X-ray diffraction, have reported the structures of the active protein complexes, and revealed unprecedented insights into the molecular mechanisms of these three enzymes.

Predictors of lenalidomide maintenance duration after autologous stem cell transplant in patients with multiple myeloma.

BACKGROUND: For patients with multiple myeloma (MM) who have undergone autologous stem cell transplant (auto-SCT), the immunomodulatory agent lenalidomide is a first-line option for maintenance therapy. Because longer durations of lenalidomide maintenance are associated with improved survival, identifying strategies to avoid premature cessation of maintenance is an important priority in the post-transplant setting. OBJECTIVES: The primary objective of this analysis was to identify specific clinical predictors of lenalidomide treatment duration that could guide optimal medication management. Key secondary objectives included predictors of intolerable toxicity, rationale for lenalidomide dose reduction/discontinuation, and characterization of dose adjustments. STUDY DESIGN: This retrospective, multi-center cohort study included adults with MM who underwent auto-SCT and initiated maintenance lenalidomide between 01/01/2012 and 02/28/2021. Variables assessed as potential predictors of maintenance duration or intolerable toxicity included age, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at time of auto-SCT, renal function, initial lenalidomide dose, use of combination maintenance therapy, and cytogenetic risk category. RESULTS: Among 299 patients included, the median age at time of auto-SCT was 62 years (range 30-77). The majority of patients had standard-risk cytogenetics (64%) and an ECOG performance status of 0 or 1 (72%). In the overall population, the median duration of maintenance was 1.3 years (range 0.3-8.6 years). The median initial dose of lenalidomide was 10 mg daily (range 2.5-25 mg). During the study period, 35% of patients had a dose reduction due to toxicity, 21% stopped lenalidomide due to disease progression, and 19% stopped due to toxicity. Multivariate linear regression analyses did not identify any significant predictors of lenalidomide duration or discontinuation due to intolerable toxicity. The most frequently reported toxicities leading to discontinuation were cytopenias, rash, and fatigue. CONCLUSION: This analysis did not identify any significant risk factors to predict the duration of lenalidomide maintenance or discontinuation for toxicity following auto-SCT in patients with MM. While limited by the retrospective design and relatively small sample size, our findings suggest that a priori lenalidomide dose reductions based on patient co-morbidities or performance status may not substantially affect the duration of lenalidomide maintenance.

Structural and Morphological Transformations of Covalent Organic Nanotubes.

Covalent organic nanotubes (CONTs) are porous one-dimensional frameworks connected through imine bonds via Schiff base condensation between aldehydes and amines. The presence of two amine groups at the ortho position in the structurally demanding tetraaminotriptycene (TAT) building block leads to multiple reaction pathways between the ditopic aldehyde and the tetratopic amine. We have synthesized five different monomers of CONT-1 by the Schiff base condensation reaction between TAT and o-anisaldehyde. The conversion of imine to imidazole bonding in a monomer is probed using NMR, mass spectrometry, and X-ray diffraction techniques. Solid-state NMR provide insights into the CONTs' structural connectivity. A theoretical investigation suggests that the π-π stacking could be the driving force for rapid imine to imidazole conversion within the CONT-1. Microscopic imaging sheds further light on the self-assembly process of the CONTs, indicating both head-to-head and side-by-side assembly.