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Abstract Ibrutinib, a Bruton's tyrosine kinase inhibitor, is often used as first‐line (1L) treatment of chronic lymphocytic leukaemia (CLL); however, it is associated with an increased risk for cardiovascular adverse events (CVAEs). This real‐world study adds to existing literature by simultaneously investigating the correlation between pre‐existing CV risk factors and the relative cardiotoxicity of ibrutinib vs other therapies in CLL/small lymphocytic lymphoma (SLL). Using a real‐world database, the risk of subsequent CVAEs (any CVAE, atrial fibrillation [AF], or hypertension) were compared among patients who received 1L ibrutinib monotherapy or another type of non‐ibrutinib therapy, grouped as intensive (IT) or non‐intensive therapy (NIT). Each patient's baseline CV risk was estimated using the Framingham risk score. Inverse probability treatment weighting was incorporated into a logistic regression model to reduce baseline imbalance. Results showed ibrutinib was significantly associated with higher risk of CVAEs regardless of baseline CV risk. Compared with IT, odds ratios of any CVAE, hypertension, or AF were 2.61, 3.66, and 3.02, respectively vs 1.88, 2.13, and 2.46, respectively, with NIT. Sensitivity analyses confirmed the findings were robust. These results suggest clinical caution should be taken when selecting ibrutinib for patients with CLL/SLL, especially in those with high baseline CV risk.

Characterizing the chemistry of complex organic molecules (COMs) at the epoch of planet formation provides insights into the chemical evolution of the interstellar medium (ISM) and the origin of organic materials in our solar system. We report a detection of dimethyl ether (CH _3 OCH _3 ) in the disk around the Herbig Ae star MWC 480 with sensitive Atacama Large Millimeter/submillimeter Array observations. This is the first detection of CH _3 OCH _3 in a nontransitional Class II disk. The spatially unresolved, compact (≲25 au in radius) nature, broad line width (∼30 km s ^−1 ), and high excitation temperature (∼200 K) indicate the sublimation of COMs in the warm inner disk. Despite the detection of CH _3 OCH _3 , methanol (CH _3 OH), the most abundant COM in the ISM, has not been detected, from which we constrain the column density ratio of CH _3 OCH _3 /CH _3 OH ≳ 7. This high ratio may indicate the reprocessing of COMs during the disk phase, as well as the effect of the physical structure in the inner disk. We also find that this ratio is higher than in COM-rich transition disks recently discovered. This may indicate that in the full disk of MWC 480, COMs have experienced substantial chemical reprocessing in the innermost region, while the COM emission in the transition disks predominantly traces the inherited ice sublimating at the dust cavity edge located at larger radii (≳20 au).

Millimeter wavelength observations of Class II protoplanetary disks often display strong emission from hydrocarbons and high CS/SO values, providing evidence that the gas-phase C/O ratio commonly exceeds 1 in their outer regions. We present new NOEMA observations of CS 5–4, SO 7 _6 –6 _5 and 5 _6 –4 _5 , C _2 H N = 3–2, HCN 3–2, HCO ^+ 3–2, and H ^13 CO ^+ 3–2 in the DR Tau protoplanetary disk at a resolution of ∼0.″4 (80 au). Estimates for the disk-averaged CS/SO ratio range from ∼0.4 to 0.5, the lowest value reported thus far for a T Tauri disk. At a projected separation of ∼180 au northeast of the star, the SO moment maps exhibit a clump that has no counterpart in the other lines, and the CS/SO value decreases to

Ionization drives important chemical and dynamical processes within protoplanetary disks, including the formation of organics and water in the cold midplane and the transportation of material via accretion and magnetohydrodynamic flows. Understanding these ionization-driven processes is crucial for understanding disk evolution and planet formation. We use new and archival Atacama Large Millimeter/submillimeter Array observations of HCO ^+ , H ^13 CO ^+ , and N _2 H ^+ to produce the first forward-modeled 2D ionization constraints for the DM Tau protoplanetary disk. We include ionization from multiple sources and explore the disk chemistry under a range of ionizing conditions. Abundances from our 2D chemical models are postprocessed using non-LTE radiative transfer, visibility sampling, and imaging, and are compared directly to the observed radial emission profiles. The observations are best fit by a modestly reduced cosmic-ray ionization rate ( ζ _CR ∼10 ^−18 s ^−1 ) and a hard X-ray spectrum (hardness ratio = 0.3), which we associate with stellar flaring conditions. Our best-fit model underproduces emission in the inner disk, suggesting that there may be an additional mechanism enhancing ionization in DM Tau’s inner disk. Overall, our findings highlight the complexity of ionization in protoplanetary disks and the need for high-resolution multiline studies.

Rings and gaps are among the most widely observed forms of substructure in protoplanetary disks. A gap–ring pair may be formed when a planet carves a gap in the disk, which produces a local pressure maximum following the gap that traps inwardly drifting dust grains and appears as a bright ring owing to the enhanced dust density. A dust-trapping ring would provide a promising environment for solid growth and possibly planetesimal production via the streaming instability. We present evidence of dust trapping in the bright ring of the planet-hosting disk Elias 2-24, from the analysis of 1.3 and 3 mm Atacama Large Millimeter/submillimeter Array observations at high spatial resolution (0.″029, 4.0 au). We leverage the high spatial resolution to demonstrate that larger grains are more efficiently trapped and place constraints on the local turbulence (8 × 10 ^−4 < α _turb < 0.03) and the gas-to-dust ratio (Σ _g /Σ _d < 30) in the ring. Using a scattering-included marginal probability analysis, we measure a total dust disk mass of ${M}_{\mathrm{dust}}={13.8}_{-0.5}^{+0.7}\times {10}^{-4}\ {M}_{\odot }$ . We also show that at the orbital radius of the proposed perturber the gap is cleared of material down to a flux contrast of 10 ^−3 of the peak flux in the disk.

Using controlled injection and recovery experiments, we devised an analysis prescription to assess the quality of dynamical measurements of protoplanetary disk gas masses based on resolved (CO) spectral line data, given observational limitations (resolution, sampling, noise), measurement bias, and ambiguities in the geometry and physical conditions. With sufficient data quality, this approach performed well for massive disks ( M _d / M _* = 0.1): we inferred M _d posteriors that recovered the true values with little bias (≲20%) and uncertainties within a factor of two (2 σ ). The gas surface density profiles for such cases are recovered with remarkable fidelity. Some experimentation indicates that this approach becomes insensitive when M _d / M _* ≲ 5%, due primarily to degeneracies in the surface density profile parameters. Including multiple lines that probe different vertical layers, along with some improvements in the associated tools, might push that practical boundary down by another factor of ∼two in ideal scenarios. We also demonstrated this analysis approach using archival Atacama Large Millimeter/Submillimeter Array observations of the MWC 480 disk: we measured ${M}_{{\rm{d}}}={0.13}_{\ -0.01}^{\ +0.04}\ {M}_{\odot }$ (corresponding to M _d / M _* = 7% ± 1%) and identified kinematic substructures consistent with surface density gaps around 65 and 135 au. Overall, this (and similar work) suggests that these dynamical measurements offer powerful new constraints with sufficient accuracy and precision to quantify gas masses and surface densities at the high end of the M _d / M _* distribution, and therefore can serve as key benchmarks for detailed thermo-chemical modeling. We address some prospects for improvements, and discuss various caveats and limitations to guide future work.

We present MIRI Medium-resolution Spectrograph observations of the large, multi-gapped protoplanetary disk around the T Tauri star AS 209. The observations reveal hundreds of water vapor lines from 4.9–25.5 μ m toward the inner ∼1 au in the disk, including the first detection of rovibrational water emission in this disk. The spectrum is dominated by hot (∼800 K) water vapor and OH gas, with only marginal detections of CO _2 , HCN, and a possible colder water vapor component. Using slab models with a detailed treatment of opacities and line overlap, we retrieve the column density, emitting area, and excitation temperature of water vapor and OH, and provide upper limits for the observable mass of other molecules. Compared to MIRI spectra of other T Tauri disks, the inner disk of AS 209 does not appear to be atypically depleted in CO _2 nor HCN. Based on Spitzer Infrared Spectrograph observations, we further find evidence for molecular emission variability over a 10 yr baseline. Water, OH, and CO _2 line luminosities have decreased by factors of 2–4 in the new MIRI epoch, yet there are minimal continuum emission variations. The origin of this variability is yet to be understood.

Among patients with chronic lymphocytic leukemia (CLL) with deletion 17p (del[17p]), evidence from clinical trials for the effectiveness of single-agent ibrutinib as first-line therapy is limited. This retrospective analysis compared real-world clinical outcomes among patients with CLL, with and without del(17p), treated with first-line ibrutinib monotherapy. Overall survival, time to next treatment, time to treatment discontinuation, and reasons for ibrutinib discontinuation were evaluated. Using data from a real-world database, patients included were aged ≥18 years, had been diagnosed with CLL between January 1, 2011 and December 31, 2019, had undergone cytogenetic testing, and had received first-line ibrutinib monotherapy. A total of 1,069 patients were included in the analysis (62.7% male; median age 69 years); 23.8% (n=254) had del(17p). The median overall survival was significantly shorter in patients with del(17p) than in patients without (57.7 months vs. not reached; P=0.0006). Similar results were observed for median time to next treatment (49.4 months vs. not reached, P=0.0330). The median time to treatment discontinuation was non-significantly shorter in the group of patients with del(17p) (32.5 months vs. 42.9 months, P=0.3370). Results of an adjusted Cox proportional hazards model showed that the group with del(17p) was at significantly higher risk of death than was the group without del(17p) (hazard ratio=1.70, P=0.0031). Event rates for switching to new treatment and discontinuation were higher but not statistically significantly so. The most common reason for discontinuing ibrutinib treatment in both groups was toxicity, but discontinuation due to progression was significantly more frequent among patients with del(17p) (20% vs. 6%; P

Abstract Background Bruton tyrosine kinase (BTK) inhibitors have demonstrated a high degree of efficacy in the treatment of B cell malignancies characterized by constitutive B cell receptor activation, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Methods The efficacy and safety of zanubrutinib, an investigational highly selective BTK inhibitor, was evaluated in this single-arm, phase 2 study of Chinese patients with relapsed/refractory CLL/SLL. The primary endpoint was overall response rate as assessed by an independent review committee. Results Of the 91 evaluable patients, 77 (84.6%) achieved a response, with three (3.3%), 54 (59.3%), and 20 (22%) patients achieving a complete response, partial response, and partial response with lymphocytosis, respectively, after a median follow-up of 15.1 months. The estimated 12-month event-free rate for duration of response was 92.9%. The most commonly reported grade ≥ 3 adverse events (AEs) were neutropenia (44%), thrombocytopenia (15.4%), lung infection/pneumonia (13.2%), upper respiratory tract infection (9.9%), and anemia (8.8%). The 12-month overall survival rate was 96%. Eight (9.0%) patients discontinued zanubrutinib due to AEs, and seven (8.0%) patients required at least one dose reduction. Conclusion Treatment of patients with relapsed/refractory CLL/SLL with zanubrutinib was generally well tolerated and resulted in a high overall response rate, thereby conferring a favorable benefit-risk profile. Trial registration Prospectively registered in China public registry (CTR20160890) on December 7, 2016: http://www.chinadrugtrials.org.cn/ . Retrospectively registered in ClinicalTrials.gov ( NCT03206918 ) on July 2, 2017.

We study the kinematics of the AS 209 disk using the J = 2–1 transitions of ^12 CO, ^13 CO, and C ^18 O. We derive the radial, azimuthal, and vertical velocity of the gas, taking into account the lowered emission surface near the annular gap at ≃1.″7 (200 au) within which a candidate circumplanetary-disk-hosting planet has been reported previously. In ^12 CO and ^13 CO, we find a coherent upward flow arising from the gap. The upward gas flow is as fast as 150 m s ^−1 in the regions traced by ^12 CO emission, which corresponds to about 50% of the local sound speed or 6% of the local Keplerian speed. Such an upward gas flow is difficult to reconcile with an embedded planet alone. Instead, we propose that magnetically driven winds via ambipolar diffusion are triggered by the low gas density within the planet-carved gap, dominating the kinematics of the gap region. We estimate the ambipolar Elsässer number, Am, using the HCO ^+ column density as a proxy for ion density and find that Am is ∼0.1 at the radial location of the upward flow. This value is broadly consistent with the value at which numerical simulations find that ambipolar diffusion drives strong winds. We hypothesize that the activation of magnetically driven winds in a planet-carved gap can control the growth of the embedded planet. We provide a scaling relationship that describes the wind-regulated terminal mass: adopting parameters relevant to 100 au from a solar-mass star, we find that the wind-regulated terminal mass is about one Jupiter mass, which may help explain the dearth of directly imaged super-Jovian-mass planets.

High-spatial-resolution observations of CO isotopologue line emission in protoplanetary disks at mid-inclinations (≈30°–75°) allow us to characterize the gas structure in detail, including radial and vertical substructures, emission surface heights and their dependencies on source characteristics, and disk temperature profiles. By combining observations of a suite of CO isotopologues, we can map the two-dimensional ( r , z ) disk structure from the disk upper atmosphere, as traced by CO, to near the midplane, as probed by less abundant isotopologues. Here, we present high-angular-resolution (≲0.″1 to ≈0.″2; ≈15–30 au) observations of CO, ^13 CO, and C ^18 O in either or both J = 2–1 and J = 3–2 lines in the transition disks around DM Tau, Sz 91, LkCa 15, and HD 34282. We derived line emission surfaces in CO for all disks and in ^13 CO for the DM Tau and LkCa 15 disks. With these observations, we do not resolve the vertical structure of C ^18 O in any disk, which is instead consistent with C ^18 O emission originating from the midplane. Both the J = 2–1 and J = 3–2 lines show similar heights. Using the derived emission surfaces, we computed radial and vertical gas temperature distributions for each disk, including empirical temperature models for the DM Tau and LkCa 15 disks. After combining our sample with literature sources, we find that ^13 CO line emitting heights are also tentatively linked with source characteristics, e.g., stellar host mass, gas temperature, disk size, and show steeper trends than seen in CO emission surfaces.

Protoplanetary disks around Herbig AeBe stars are exciting targets for studying the chemical environments where giant planets form. Save for a few disks, however, much of Herbig AeBe disk chemistry is an open frontier. We present a Submillimeter Array ∼213–268 GHz pilot survey of millimeter continuum CO isotopologs and other small molecules in disks around five Herbig AeBe stars (HD 34282, HD 36112, HD 38120, HD 142666, and HD 144432). We detect or tentatively detect ^12 CO 2–1 and ^13 CO 2–1 from four disks, C ^18 O 2–1 and HCO ^+ 3–2 from three disks, HCN 3–2, CS 5–4, and DCO ^+ 3–2 from two disks, and C _2 H 3–2 and DCN 3–2 from one disk each. H _2 CO 3–2 is undetected at the sensitivity of our observations. The millimeter continuum images of HD 34282 suggest a faint, unresolved source ∼5.″0 away, which could arise from a distant orbital companion or an extended spiral arm. We fold our sample into a compilation of T Tauri and Herbig AeBe/F disks from the literature. Altogether, most line fluxes generally increase with millimeter continuum flux. Line flux ratios between CO 2–1 isotopologs are nearest to unity for the Herbig AeBe/F disks. This may indicate emitting layers with relatively similar, warmer temperatures and more abundant CO relative to the disk dust mass. Lower HCO ^+ 3–2 flux ratios may reflect lower ionization in Herbig AeBe/F disks. Lower detection rates and flux ratios for DCO ^+ 3–2, DCN 3–2, and H _2 CO 3–2 suggest smaller regimes of cold chemistry around the luminous Herbig AeBe/F stars.

Deuterium fractionation provides a window into the thermal history of volatiles in the solar system and protoplanetary disks. While evidence of active molecular deuteration has been observed toward a handful of disks, it remains unclear whether this chemistry affects the composition of forming planetesimals due to limited observational constraints on the radial and vertical distribution of deuterated molecules. To shed light on this question, we introduce new Atacama Large Millimeter/submillimeter Array observations of DCO ^+ and DCN J = 2–1 at an angular resolution of 0.″5 (30 au) and combine them with archival data of higher energy transitions toward the protoplanetary disk around TW Hya. We carry out a radial excitation analysis assuming both LTE and non-LTE to localize the physical conditions traced by DCO ^+ and DCN emission in the disk, thus assessing deuterium fractionation efficiencies and pathways at different disk locations. We find similar disk-averaged column densities of 1.9 × 10 ^12 and 9.8 × 10 ^11 cm ^−2 for DCO ^+ and DCN, with typical kinetic temperatures for both molecules of 20–30 K, indicating a common origin near the comet- and planet-forming midplane. The observed DCO ^+ /DCN abundance ratio, combined with recent modeling results, provide tentative evidence of a gas-phase C/O enhancement within

DR Tau has been noted for its unusually high variability in comparison with other T Tauri stars. Although it is one of the most extensively studied pre-main-sequence stars, observations with millimeter interferometry have so far been relatively limited. We present NOEMA images of ^12 CO, ^13 CO, C ^18 O, SO, DCO ^+ , and H _2 CO toward DR Tau at a resolution of ∼0.″5 (∼100 au). In addition to the protoplanetary disk, CO emission reveals an envelope, a faint asymmetric outflow, and a spiral arm with a clump. The ∼1200 au extent of the CO arm far exceeds that of the spiral arms previously detected in scattered light, which underlines the necessity of sensitive molecular imaging for contextualizing the disk environment. The kinematics and compact emission distribution of C ^18 O, SO, DCO ^+ , and H _2 CO indicate that they originate primarily from within the Keplerian circumstellar disk. The SO emission, though, also exhibits an asymmetry that may be due to interaction with infalling material or unresolved substructure. The complex environment of DR Tau is reminiscent of those of outbursting FUor sources and some EXor sources, suggesting that DR Tau’s extreme stellar activity could likewise be linked to disk instabilities promoted by large-scale infall.

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 – 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 – 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 – 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 – 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

Antisense oligonucleotides are metabolized by nucleases and drug interactions with small drug molecules at either the cytochrome P450 (CYP) enzyme or transporter levels have not been observed to date. Herein, a comprehensive in vitro assessment of the drug-drug interaction (DDI) potential was carried out with four 2′-O-(2-methoxyethyl)-modified antisense oligonucleotides (2′-MOE-ASOs), including a single triantennary N-acetyl galactosamine (GalNAc3)-conjugated ASO. Several investigations to describe the DDI potential of a 2′-MOE-ASO conjugated to a high-affinity ligand for hepatocyte-specific asialoglycoprotein receptors are explored. The inhibition on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 and induction on CYP1A2, CYP2B6, and CYP3A4 were investigated in cryopreserved hepatocytes using up to 100 μM of each ASO. No significant inhibition (half maximal inhibitory concentration [IC50] > 100 μM) or induction was observed based on either enzymatic phenotype or mRNA levels. In addition, transporter interaction studies were conducted with nine major transporters per recommendations from regulatory guidances and included three hepatic uptake transporters, organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3; three renal uptake transporters, organic anion transporter 1 (OAT1), OAT3, and OCT2; and three efflux transporters, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and bile salt export pump (BSEP). None of the four ASOs (10 μM) were substrates of any of the nine transporters, with uptake

Toona sinensis is a common edible vegetable that is used in certain Chinese dishes and has importance in folk medicine. The leaf extracts of T sinensis possess and exhibit anticancer efficacy against various cancer cell types. In Taiwanese folklore, Antrodia camphorata , also known as “Niu-Cheng-Zi,” is used in traditional medicine to treat various illnesses. Its fruit and mycelium possess various potent antiproliferative properties. Two studies from our group have reported that T sinensis or A camphorata has the ability to cause apoptosis in various cancer cells. Conversely, underlying molecular mechanisms and any beneficial effects remain unknown. This study shows anticancer efficacy for both T sinensis and A camphorata co-treatments that target HL-60 cells. The combination index values indicate that 40 µg/mL of T sinensis and 25 µg/mL of A camphorata as a combined treatment shows a synergetic effect, which reduces HL-60 cell proliferation. Alternately, this treatment exhibited no cytotoxic effects for human umbilical vein endothelial cells. Western blot data showed that T sinensis and A camphorata as a combined treatment result in augmented expression of apoptosis, cytochrome c release, Bcl-2 inhibition, expression of Bax, Fas, and FasL, as well as the cleavage of Bid in HL-60 cells. Moreover, this combined treatment overshadowed monotherapy in its ability to inhibit uPAR, MMP-9, MMP-2, COX-2 expression, and PGE 2 secretions. Our study strongly implies that this combined treatment offers more beneficial effects to suppress and treat leukemia due to apoptosis-mediated cell inhibition. Further in vivo studies related to the combined treatment could establish its future potential.