Browse Articles

High-Rate, Selective Electrosynthesis of Cyclohexanone Oxime via In Situ Generation and Release of Hydroxylamine on Bismuth

Inductor-capacitor gain cell-based non-isolated high step-up converter for DC microgrid

Progression-free survival after next line of treatment (PFS2) and subsequent therapies (subs tx) in the ASCENT-04 study of participants (pts) with previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC) treated with sacituzumab govitecan (SG) plus pembrolizumab (pembro) vs chemotherapy (chemo) plus pembro.

LBA1000 Background: In ASCENT-04, first-line (1L) SG + pembro led to a statistically significant and clinically meaningful improvement in PFS vs chemo + pembro (median, 11.2 vs 7.8 mo; hazard ratio [HR], 0.65; 95% CI, 0.51-0.84; P < .001) in pts with previously untreated PD-L1+ mTNBC. Overall survival (OS) data are immature. PFS2 is more strongly associated with OS than PFS and can be used to measure long-term clinical benefit in the absence of mature OS data or when OS may be impacted by crossover. We report PFS2 and subs tx from ASCENT-04. Methods: Pts (N = 443) were randomized 1:1 to SG (10 mg/kg IV, days 1 & 8) + pembro (200 mg, day 1, max 35 cycles) in 21-day cycles or chemo (gemcitabine + carboplatin, paclitaxel, or nab-paclitaxel) + pembro; the primary end point was PFS by blinded independent central review (BICR). Eligible pts in the chemo + pembro group could receive 2L SG provided on study via crossover following BICR-verified progressive disease (PD) or in any subs line commercially; other subs txs per local practice were also permitted. PFS2 was defined as the time from randomization to first documented PD on next-line therapy per investigator assessment or death due to any cause, whichever occurred first. Results: Median follow-up for OS was 14.0 mo; 95 (43%) pts remained on study tx in the SG + pembro group (n = 221) and 52 (23%) in the chemo + pembro group (n = 222). Of the 125 pts in the SG + pembro group who discontinued tx, 69 received any subs tx, the most frequent of which were taxanes (42%), platinum chemo (33%), and capecitabine (33%). Of the 170 pts in the chemo + pembro group who discontinued tx, 119 received any subs tx, the most frequent of which were SG (81%), taxanes (9%), and capecitabine (9%). Median PFS2 and PFS2 rates are in the Table. Median (95% CI) time to first subs tx was 17.3 mo (12.7-not reached [NR]) for SG + pembro and 9.8 mo (8.7-10.9) for chemo + pembro; median (95% CI) time to second subs tx was NR (22.9 mo-NR) and 21.0 mo (16.6-NR). Conclusions: PFS2 was improved in the SG + pembro group vs chemo + pembro group despite crossover tx, with most pts who initiated subs tx in the chemo + pembro group receiving SG. In pts with previously untreated PD-L1+ mTNBC, SG + pembro provided clinically relevant continued benefit beyond first progression, further supporting SG + pembro as a potential new standard of care. Clinical trial information: NCT05382286 . SG + pembro Chemo + pembro Pts with PFS2 events, n/N (%) 55/221 (25) 83/222 (37) Median PFS2 (95% CI), mo NR (NR-NR) 21.0 (16.0-NR) Stratified HR a (95% CI) 0.67 (0.48-0.95) Stratified log-rank nominal P -value a .0224 PFS2 rate (95% CI), % 12 mo 80.0 (73.8-84.9) 75.7 (69.1-81.1) 18 mo 71.9 (64.5-78.0) 53.0 (44.5-60.8) 24 mo 63.7 (51.1-73.9) 45.6 (35.6-55.1) a SG + pembro vs chemo + pembro.

Divergent C2 functionalization of N-Heteroarenes via nonclassical rearomatization

Realization of Self-Terminating Underpotential Electropolymerization by Strong Supramolecular Monomer-Electrode Interaction

Autonomic impairment in advanced heart-failure patients revealed by nonlinear heart rate variability measured during exercise

Nationwide randomized, phase III, placebo-controlled trial of bupropion for cancer-related fatigue: Primary outcome results.

LBA12003 Background: Fatigue is common and debilitating among people with cancer. Treatment options for cancer-related fatigue are limited. Methylphenidate demonstrates limited efficacy and low tolerability. Behavioral interventions include exercise and cognitive-behavioral therapy, which many individuals may be unwilling or unable to adopt. Additional therapies are needed. Bupropion has been shown to reduce two hypothesized mechanisms of cancer-related fatigue (CRF), systemic inflammation and hypothalamic pituitary adrenal (HPA) axis functioning. A large-scale, placebo-controlled evaluation of bupropion is needed to offer a potential new therapeutic option for CRF. Methods: The trial was conducted through the University of Rochester Cancer Center National Cancer Institute Community Oncology Research Program (URCC NCORP) Research Base and member sites across the U.S. Eligible patients were adults with any stage or site of disease who reported moderate to severe worst fatigue (i.e., score of 4 or above on 0-10 scale) in past week and had no reported or documented contraindication to bupropion. They completed surgery, radiation, and/or intravenous (IV) anticancer therapy at least two months prior to enrollment. Individuals receiving oral therapies or IV supportive therapy were eligible. Participants were randomized 1:1 to receive over-encapsulated 150 mg bupropion or a placebo. They were instructed to take one capsule in week 1, two capsules in weeks 2-12, and one capsule in week 13. The primary outcome was group differences in the FACIT-F fatigue subscale score at week 12. ANCOVA was conducted with group as the main factor and baseline FACIT-F score as a covariate. Study site was included as a random effect independent of residual error. The study was designed with a statistical power of 90% to identify a difference of 0.30 SD in the FACIT-F score, which corresponds to a clinically meaningful change. Results: Participants (N = 428) had a mean age of 61 years (SD = 12). Most were female (83%), white (86%), non-Hispanic (93%), and/or diagnosed with breast cancer (73%). There were no baseline group differences in demographic, clinical, or fatigue variables ( p values>0.13), except the bupropion group was less likely to have received radiation (65% vs. 74%, p = 0.05). Intent-to-treat analyses indicated that bupropion significantly reduced fatigue (Cohen’s d = 0.23, p = 0.03) relative to placebo. Prespecified moderator analyses indicated that bupropion was associated with significant improvements in fatigue in women (Cohen’s d = 0.33, p = 0.006) but not men ( p = 0.24). Conclusions: In this large, phase III, community-based trial, bupropion resulted in modest reductions in fatigue relative to placebo, particularly among women. Bupropion should be considered in the pharmacologic management of CRF. Clinical trial information: NCT03996265 .

Mechanistic insights into activation of bacterial Retron-Eco8 immunity by phage protein SSB

Green synthesis of cadmium sulfide quantum dots coated with quercus infectoria and Heracleum persicum: cytotoxicity studies on RBCs and HFF-2 cells

Quizartinib for Newly Diagnosed <i>FLT3</i> -Internal Tandem Duplication–Negative AML

Pharmacokinetics, bactericidal activity and toxicity of short oral regimens for rifampicin-resistant tuberculosis treatment

Abstract The exposure and both Mycobacterium tuberculosis clearance rates and toxicity relationships of bedaquiline-pretomanid-linezolid- (BPaL), BPaL-clofazimine (BPaLC) and BPaL-moxifloxacin (BPaLM) for treatment of rifampicin-resistant tuberculosis remain understudied. Therefore, the relationship between the patients’ exposure to anti-TB drugs in TB-PRACTECAL trial investigational regimens and their treatment outcomes was investigated. PRACTECAL-PKPD was a prospective pharmacokinetics and pharmacodynamics study. Patients with rifampicin-resistant tuberculosis were enrolled from Belarus and South Africa. Antimicrobial exposures for bedaquiline, pretomanid, linezolid, moxifloxacin and clofazimine were adequately estimated, were within the ranges of previously published studies but did not correlate with the speed of sputum bacterial clearance. When compared to the standard of care (SoC) arm, a 20% increased bacillary killing rate with BPaLM was observed, whilst BPaL and BPaLC displayed a 15% decreased rate. Also of note was a 20% decreased bacillary killing rate in patients with severe disease irrespective of treatment. Linezolid exposure was higher amongst patients with anaemia or neutropenia. No other exposure-toxicity relationships were identified for all other drugs. These data indicate that the studied doses of linezolid and moxifloxacin could be the right balance between effectiveness and safety, strengthening the WHO recommendation that BPaLM is the preferred regimen for rifampicin-resistant tuberculosis in adolescents and adults. The study was registered in Clinical Trials.gov, TRN: NCT04081077.

Tuning *OH Oxidativity via a Cu–Co(OH) ₂ Cocatalyst on a Hematite Photoanode for Selective Cyclohexanone Oxidation

Adaptive filtering method for reducing signal saturation induced artifacts in X-ray dark-field tomography

Abstract X-ray dark-field imaging provides information of an object based on its small-angle scattering properties. Dark-field contrast originates from differences in the strength of scattering from micron and sub-micron sized structures in the object. A Talbot-Lau interferometer can be utilized for dark-field imaging with regular X-ray tubes. A known difficulty with the method arises, when the scattering is too strong, preventing the dark-field and phase retrieval to work accurately. This is similar to a strongly absorbing object in attenuation-based X-ray imaging, and causes problems in tomographic reconstruction that depends on the accuracy of the projected signal. In this article, we present an adaptive filtering approach for the dark-field and phase-contrast projections to improve the signal-to-noise ratio in image areas where the dark-field signal is close to saturation. This filtering improves the projection images markedly, and enables tomographic reconstruction even in cases where the sample contains strong scatterers.

Yttrium-90 Radioembolization Provides Durable Local Control and Definitive Radiation Therapy

Bioresorbable electrochemical sensors for continuous deep-tissue lactate monitoring in critical care

A Vibrational Probe of Electrical Doping in N2200 and Fermi-Level Alignment at Polymer Cathode/Metal Cocatalyst/Electrolyte Junctions

Association between the lifelines diet score and the odds of prediabetes and type 2 diabetes mellitus in Iranian adults: a cross-sectional study

Mezigdomide, carfilzomib, and dexamethasone (MeziKd) vs carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): Results from the phase 3 SUCCESSOR-2 trial.

LBA7506 Background: A growing number of patients (pts) entering second-line treatment (tx) are anti-CD38 monoclonal antibody (mAb)- and lenalidomide (LEN)-exposed, limiting tx options. Mezigdomide (Mezi), a potent oral CELMoD, induces maximal, rapid Ikaros/Aiolos degradation leading to enhanced MM cell death and immune stimulation vs IMiDs. We report initial results from SUCCESSOR-2 (NCT05552976), the first randomized phase 3 study of Mezi in RRMM, evaluating MeziKd vs Kd. Methods: In this phase 3, 2-stage, inferentially seamless trial, eligible adult pts had ≥1 prior line of therapy (LOT) including an anti-CD38 mAb and LEN. Pts were randomized 3:3:3:2 (Mezi 0.3, 0.6, 1.0 mg + Kd, or Kd) to identify the optimal Mezi dose in stage 1, and 3:2 to compare efficacy and safety of MeziKd vs Kd in stage 2. MeziKd was given in 28-day (D) cycles of Mezi (D1–21), 56 mg/m 2 carfilzomib (CFZ) weekly (QW), and 40 mg dexamethasone (DEX) QW. The Kd arm received CFZ 56 mg/m 2 twice weekly or 70 mg/m 2 QW + DEX. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, selected Mezi dose (stage 1), overall response rate (ORR), and safety. Results: The Mezi dose selected for stage 2 was 1.0 mg. In total, 479 pts (288 MeziKd at 1.0 mg Mezi; 191 Kd) were included in the analysis. Median (range) age was 68 (30–85) y with 25.1% of pts ≥75 y; median (range) number of prior LOTs was 2 (1–9); 92.1% of pts were triple-class-exposed, with 85.8% refractory to an anti-CD38 mAb and 75.8% to LEN; 37.2% were exposed to pomalidomide and 7.3% to anti-BCMA tx. At data cutoff, median follow-up was 10.6 mo with 52.4% (MeziKd) and 31.4% (Kd) of pts still on tx. Median tx duration was 8.9 (up to 32.1) mo for MeziKd vs 6.2 (up to 25.0) for Kd. MeziKd significantly improved PFS vs Kd (median [95% CI], 18.0 [14.5–22.1] vs 8.3 [5.6–10.7] mo; HR, 0.48 [95% CI, 0.36–0.63]; P &lt;0.0001), which was consistent across subgroups, including pts with &gt;2 prior LOTs, prior tx exposure/refractoriness, high-risk cytogenetics, extramedullary disease, and age ≥75 y. Higher ORR (80.2% vs 53.4%) and complete response or better (26.7% vs 8.9%) were seen with MeziKd. Deaths were reported in 21.5% (MeziKd) vs 26.7% (Kd) of pts, mostly due to progressive disease. Grade (Gr) 3–4 treatment-emergent adverse events were seen in 83.7% vs 56.5% of pts, neutropenia in 61.1% vs 9.1%, and infections in 34.0% vs 15.6% with MeziKd and Kd, respectively; Gr 5 infections in this high-risk population were few (2.4 vs 1.1%). Conclusions: MeziKd showed a clinically meaningful PFS benefit as early as first relapse in predominantly triple-class-exposed, anti-CD38 mAb- and LEN-refractory pts, a population with significant unmet need. These data support Mezi, a potent oral tx with a predictable and manageable safety profile, as a readily accessible, potential new standard of care for RRMM across multiple settings. Clinical trial information: NCT05552976 .

Efficient and durable light-alkane oxidation over sintered Pt catalysts

High-Entropy Alloy Aerogels with High-Density Solid–Solid Heterointerfaces for Alkaline Hydrogen Evolution