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

Covalent organic frameworks (COFs) are two-dimensional, crystalline porous framework materials with numerous scopes of tunability like 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 review, we have discussed both top-down (COFs→CONs) and bottom-up (molecules→CONs) with precise information on thickness and lateral growth. We have showcased the research progress of CONs in few selected applications like batteries, catalysis, sensing and biomedical applications. This review specifically highlights the reports where the authors compare the performance of CONs with COFs by demonstrating the impact of thickness and lateral growth of the nanosheets. Eventually, we have provided the possible scope of exploration of CONs research in terms of inter-dimensional conversion like graphene to carbon nanotube and future technologies..

Optimizing Autologous Stem Cell Transplantation in Multiple Myeloma: The Impact of Intensive Chemomobilization.

BACKGROUND: Most transplant-eligible multiple myeloma (MM) patients undergo autologous peripheral blood stem cell collection (PBSC) using G-CSF with on-demand plerixafor (G±P). Chemomobilization (CM) can be used as a salvage regimen after G±P failure or for debulking residual tumor burden ahead of autologous peripheral blood stem cell transplantation (ASCT). Prior studies utilizing cyclophosphamide-based CM have not shown long-term benefit. OBJECTIVES: At our center, intensive CM (ICM) using a PACE- or HyperCVAD-based regimen has been used to mitigate "excessive" residual disease based on plasma cell burden or MM-related biomarkers. Given the lack of efficacy of non-intensive CM, we sought to determine the impact of ICM on event-free survival (EFS), defined as death, progressive disease, or unplanned treatment escalation. STUDY DESIGN: We performed a retrospective study of newly diagnosed MM patients who collected autologous PBSCs with the intent to proceed immediately to ASCT at our center between 7/2020 and 2/2023. Patients were excluded if they underwent a tandem autologous or sequential autologous-allogeneic transplant, had primary plasma cell leukemia, received non-ICM treatment (i.e., cyclophosphamide and/or etoposide), or had previously failed G±P mobilization. To appropriately evaluate the impact of ICM among those who potentially could have received it, we utilized a propensity score matching (PSM) approach whereby ICM patients were compared to a cohort of non-CM patients matched on pre-ASCT factors most strongly associated with the receipt of ICM. RESULTS: Of 451 patients identified, 61 (13.5%) received ICM (PACE-based, n=45; hyper-CVAD-based, n=16). Post-ICM/pre-ASCT, 11 patients (18%) required admission for neutropenic fever and/or infection. Among 51 evaluable patients, the overall response rate was 31%; however, 46 of 55 evaluable patients (84%) saw a reduction in M-spike and/or involved FLCs. Among those evaluated with longitudinal peripheral blood flow cytometry (n=8), 5 patients (63%) cleared circulating blood PCs post-ICM. Compared to patients mobilized with non-CM, ICM patients collected a slightly greater median number of CD34+ cells (10.8 vs 10.2 × 106/kg, p=.018). The median follow-up was 30.6 months post-ASCT. In a PSM multivariable analysis, ICM was associated with significantly improved EFS (HR 0.30, 95% CI 0.14 to 0.67, p=.003), but not improved OS (HR 0.38, 95% CI 0.10 to 1.44, p=.2). ICM was associated with longer post-ASCT inpatient duration (+4.1 days, 95% CI, 2.4 to 5.8, p<.001), more febrile days (+0.96 days, 95% CI 0.50 to 1.4, p<.001), impaired platelet engraftment (HR 0.23, 95% CI 0.06 to 0.87, p=.031), more bacteremia (OR 3.41, 95% CI 1.20 to 9.31, p=.018), and increased antibiotic usage (cefepime: +2.3 doses, 95% CI 0.39 to 4.1, p=.018; vancomycin: +1.0 doses, 95% CI 0.23 to 1.8, p=.012). CONCLUSIONS: ICM was independently associated with improved EFS in a matched analysis involving MM patients with excessive disease burden at pre-ASCT workup. This benefit came at the cost of longer inpatient duration, more febrile days, greater incidence of bacteremia, and increased antibiotic usage in the immediate post-ASCT setting. Our findings suggest that ICM could be considered for a subset of MM patients, but its use must be weighed carefully against additional toxicity.

Mitigating time toxicity in lymphoma and multiple myeloma.

The concept of time toxicity in oncology refers to the presence of frequent healthcare-related interactions that can interfere with patient well-being. In this review, we examine several manifestations of time toxicity in non-Hodgkin lymphoma and multiple myeloma and discuss their impact on decision-making with patients. For example, time toxicity may influence the choice of chemoimmunotherapy versus lenalidomide-rituximab in follicular lymphoma. In myeloma, it may inform the optimal dosing schedule for proteasome inhibitors and bisphosphonates. In both malignancies, varying time toxicity profiles are a key distinction between chimeric antigen receptor T-cell therapies and bispecific antibodies. We outline the challenges with measuring time toxicity as a trial endpoint but discuss its importance as a consideration for patient care, both in standard-of-care settings and in clinical trials. Throughout the review, we highlight strategies to lower the time toxicity of therapies in lymphoma and myeloma without compromising their efficacy or patient safety.

Intrathecal ropivacaine versus bupivacaine in a non-obstetric population- A meta-analysis and trial sequential analysis.

Background and Aims: Intrathecal bupivacaine is used for anaesthesia and analgesia but is associated with hypotension. Ropivacaine is an alternative drug that may have fewer cardiotoxic and neurotoxic events. This meta-analysis investigated whether intrathecal ropivacaine is associated with reduced hypotension as compared to bupivacaine. Methods: The meta-analysis is registered in the International Prospective Register of Systematic Reviews (PROSPERO). The databases PubMed, Cinahl Plus, Google Scholar, and Scopus were searched, and papers from January 1980 to January 2023 were deemed eligible and filtered using predetermined inclusion and exclusion criteria. The primary outcome was the incidence of hypotension. Secondary outcomes were the duration of sensory block, duration of motor block, incidence of bradycardia, ephedrine usage, and duration of analgesia. Jadad scores were used to evaluate the quality of the papers. RevMan statistical software® utilised inverse variance and a random effect model to calculate the standardised mean difference with 95% confidence intervals for continuous variables and the Mantel-Haenszel test and the random effect model to calculate the odds ratio for dichotomous variables. Results: Thirty-three papers, including 2475 patients in total, were included. The Jadad score was between 1 and 5. The incidence of hypotension was significantly higher with intrathecal bupivacaine than with ropivacaine (P = 0.02). The duration of sensory block (P < 0.001) and motor block (P < 0.001) was prolonged with intrathecal bupivacaine. The duration of analgesia favoured intrathecal bupivacaine (P = 0.003). Conclusion: Intrathecal ropivacaine has a reduced incidence of hypotension and a reduced duration of sensory block compared to bupivacaine.

Financial Toxicity, Time Toxicity, and Quality of Life in Multiple Myeloma.

BACKGROUND: Patients with multiple myeloma (MM) may be on therapy for years, which can lead to financial toxicity (FinTox) or time toxicity (TimeTox). The prevalence, predictors, and quality of life (QOL) impacts of FinTox and TimeTox during different phases of MM treatment have not been characterized. PATIENTS AND METHODS: We conducted a single-center cross-sectional survey of patients with MM who had undergone transplantation. FinTox+ was defined as a COST-FACIT score <23, TimeTox+ as MM-related interactions (including phone calls) ≥1x weekly or ≥1x monthly in-person among far-residing patients, QOL using PROMIS Global Health, and functional status using patient-reported Karnofsky performance status (KPS). RESULTS: Of 252 patients, 22% and 40% met FinTox+ and TimeTox+ criteria respectively. Respective FinTox+ and TimeTox+ proportions were 22%/37% for patients on maintenance, 22%/82% with active therapy, and 20%/14% with observation. FinTox+ predictors included annual income (P < .01) and out-of-pocket costs (P < .01). TimeTox+ predictors included disease status (P < .001), caregiver status (P = .01), far-residing status (P < .001), and out-of-pocket costs (P = .03). FinTox+ was associated with a clinically meaningful decrease in mental QOL, while TimeTox+ patients were more likely to have KPS ≤ 80. CONCLUSIONS: In our large study, monetary status but not disease status predicted FinTox. Over a third of patients on maintenance reported TimeTox. FinTox+ was associated with decreased mental health, while TimeTox+ was associated with worse performance status. These two toxicities may negatively impact patient wellbeing, and studies of strategies to mitigate their impact are in development.

Once-weekly versus twice-weekly bortezomib in newly diagnosed multiple myeloma: a real-world analysis.

Induction regimens for multiple myeloma (MM) commonly include bortezomib, which has typically been administered twice weekly despite studies demonstrating comparable efficacy and less peripheral neuropathy (PN) with once-weekly bortezomib. We aimed to analyze the real-world prevalence and efficacy of once-weekly versus twice-weekly bortezomib regimens in newly diagnosed MM. We analyzed 2497 US patients aged 18-70 years treated with commercial first-line bortezomib using nationwide Flatiron Health electronic health record-derived data, including 910 (36.4%) patients who received twice-weekly and 1522 (63.2%) who received once-weekly bortezomib. Once-weekly bortezomib use increased over time, from 57.7% in 2017 to 73.1% in 2022. Multivariate analysis identified worsened performance status and more recent year of diagnosis with higher odds of receiving once-weekly bortezomib. Real-world progression-free survival (median 37.2 months with once-weekly versus 39.6 months with twice-weekly, p = 0.906) and overall survival (medians not reached in either cohort, p = 0.800) were comparable. PN rates were higher in patients receiving twice-weekly bortezomib (34.7% versus 18.5%, p < 0.001). In conclusion, once-weekly bortezomib is clearly associated with similar efficacy and fewer toxicities compared to twice-weekly bortezomib. Our findings support once-weekly bortezomib as a standard-of-care regimen for newly diagnosed patients with MM.

Salvage therapies including retreatment with BCMA-directed approaches after BCMA CAR-T relapses for multiple myeloma.

ABSTRACT: For patients with relapsed/refractory multiple myeloma with a relapse after B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell therapy (CAR-T), optimal salvage treatment strategies remain unclear. BCMA-directed CAR-T and bispecific antibodies (BsAbs) are now commercially available, and the outcomes for retreatment with BCMA-directed approaches are not well studied. We performed a retrospective analysis of 68 patients with relapsed disease after BCMA-directed CAR-T to evaluate outcomes and responses to salvage therapies. With a median follow-up of 13.5 months, median overall survival from time of relapse until death was 18 months (95% confidence interval [CI], 13.2 to not reached [NR]). Fifty-eight patients received subsequent myeloma-directed therapies, with a total of 265 lines of therapy (LOTs). The overall response rate for firstline salvage therapy was 41% (95% CI, 28-55). Among all LOTs, high response rates were observed among those receiving another BCMA-directed CAR-T (89%), BCMA-directed BsAbs (60%), CD38-directed combinations (80% when combined with BsAb; 50% when combined with immunomodulatory drugs and/or proteasome inhibitors), and alkylator-combinations (50% overall; 69% with high-dose alkylators). Thirty-four patients received at least 1 line of salvage BCMA-directed therapy; median progression-free survival was 8.3 months (95% CI, 7.9 to NR), 3.6 months (95% CI, 1.4 to NR), and 1 month (95% CI, 0.9 to NR) with median duration of response (DOR) of 8 months, 4.4 months, and 2.8 months for subsequent BCMA-directed CAR-T, BsAb, and belantamab mafadotin, respectively. Retreatment with BCMA-directed CAR-T and BsAbs can be effective salvage options after BCMA-directed CAR-T relapse; however, DORs appear limited, and further studies with new combinations and alternative targets are warranted.

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 .

Functionality Modulation Toward Thianthrene-based Metal-Free Electrocatalysts for Water Splitting.

The development of metal-free bifunctional electrocatalysts for hydrogen and oxygen evolution reactions (HER and OER) is significant but rarely demonstrated. Porous organic polymers (POPs) with well-defined electroactive functionalities show superior performance in hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). Precise control of the active sites' local environment requires careful modulation of linkers through the judicious selection of building units. Here, a systematic strategy is introduced for modulating functionality to design and synthesize a series of thianthrene-based bifunctional sp2 C═C bonded POPs with hollow spherical morphologies exhibiting superior electrocatalytic activity. This precise structural tuning allowed to gain insight into the effects of heteroatom incorporation, hydrophilicity, and variations in linker length on electrocatalytic activity. The most efficient bifunctional electrocatalyst THT-PyDAN achieves a current density of 10 mA cm─2 at an overpotential (η10) of ≈65 mV (in 0.5 m H2SO4) and ≈283 mV (in 1 m KOH) for HER and OER, respectively. THT-PyDAN exhibits superior activity to all previously reported metal-free bifunctional electrocatalysts in the literature. Furthermore, these investigations demonstrate that THT-PyDAN maintains its performance even after 36 h of chronoamperometry and 1000 CV cycling. Post-catalytic characterization using FT-IR, XPS, and microscopic imaging techniques underscores the long-term durability of THT-PyDAN.

Morphology Tuning via Linker Modulation: Metal-Free Covalent Organic Nanostructures with Exceptional Chemical Stability for Electrocatalytic Water Splitting.

The development of synthetic routes for the formation of robust porous organic polymers (POPs) with well-defined nanoscale morphology is fundamentally significant for their practical applications. The thermodynamic characteristics that arise from reversible covalent bonding impart intrinsic chemical instability in the polymers, thereby impeding their overall potential. Herein, a unique strategy is reported to overcome the stability issue by designing robust imidazole-linked POPs via tandem reversible/irreversible bond formation. Incorporating inherent rigidity into the secondary building units leads to robust microporous polymeric nanostructures with hollow-spherical morphologies. An in-depth analysis by extensive solid-state NMR (1D and 2D) study on 1H, 13C, and 14N nuclei elucidates the bonding and reveals the high purity of the newly designed imidazole-based POPs. The nitrogen-rich polymeric nanostructures are further used as metal-free electrocatalysts for water splitting. In particular, the rigid POPs show excellent catalytic activity toward the oxygen evolution reaction (OER) with long-term durability. Among them, the most efficient OER electrocatalyst (TAT-TFBE) requires 314 mV of overpotential to drive 10 mA cm-2 current density, demonstrating its superiority over state-of-the-art catalysts (RuO2 and IrO2).

Opportunity Strikes for Reducing Cancer Drug Waste: Bortezomib as an Example of Vial Mis-Sizing in Oncology.

Mis-sized packaging leads to millions of dollars in drug waste annually. Now is the time to act.

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.

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.

Definers and drivers of functional high-risk multiple myeloma: insights from genomic, transcriptomic, and immune profiling.

Traditional prognostic models for newly diagnosed patients with multiple myeloma (MM), including International Staging System criteria and number of high-risk chromosomal abnormalities, are based on disease characteristics at diagnosis. However, the identification of patients at risk of more rapidly progressive MM is inherently a dynamic assessment. In a subset of patients with MM, adverse disease biology only becomes evident after the failure of first-line therapy. We define this entity as functional high-risk MM (FHRMM), encompassing relapse within 18 months of treatment initiation and/or within 12 months of frontline autologous stem cell transplantation. FHRMM is not adequately captured by traditional prognostic models, and there is a need for better understanding of mechanisms or risk factors for early relapse or progression. In this review, we explore potential definitions of FHRMM before delving into its underlying drivers based on genetic, transcriptomic, and immune cell profiling studies. Emerging data suggest that specific features of both myeloma cells and immune cells can enable the FHRMM phenotype. We conclude our review by discussing ongoing and future studies that seek to identify and intervene upon patients with FHRMM preemptively.

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.