Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence.
We conducted a multicenter, ...retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS).
A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1–60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line hazard ratios (HR) 2.8, CI 1.3–6.3, P = 0.01, relapsed-refractory (HR 2.8, CI 1.9–4.1, P < 0.001), del17p (HR 2.0, CI 1.2–3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2–5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3–1.0, P = 0.06).
In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.
Despite being one of the most promising candidates for grid‐level energy storage, practical aqueous zinc batteries are limited by dendrite formation, which leads to significantly compromised safety ...and cycling performance. In this study, by using single‐crystal Zn‐metal anodes, reversible electrodeposition of planar Zn with a high capacity of 8 mAh cm−2 can be achieved at an unprecedentedly high current density of 200 mA cm−2. This dendrite‐free electrode is well maintained even after prolonged cycling (>1200 cycles at 50 mA cm−2). Such excellent electrochemical performance is due to single‐crystal Zn suppressing the major sources of defect generation during electroplating and heavily favoring planar deposition morphologies. As so few defect sites form, including those that would normally be found along grain boundaries or to accommodate lattice mismatch, there is little opportunity for dendritic structures to nucleate, even under extreme plating rates. This scarcity of defects is in part due to perfect atomic‐stitching between merging Zn islands, ensuring no defective shallow‐angle grain boundaries are formed and thus removing a significant source of non‐planar Zn nucleation. It is demonstrated that an ideal high‐rate Zn anode should offer perfect lattice matching as this facilitates planar epitaxial Zn growth and minimizes the formation of any defective regions.
Zinc‐metal anodes, which are desirable for various aqueous zinc battery chemistries, degrade over repeated cycling due to dendrite growth. It is found that dendrites can be prevented by ensuring no defective regions form during zinc deposition, thus removing sites for dendrite nucleation and ensuring purely planar deposition. This allows unprecedentedly high charging rates to be achieved.
In this brief, the high-quality carbon nanotubes (CNTs) is grown by a chemical vapor deposition (CVD) method, and it is used as an ultrafine flip-chip interconnection material in the proposed 3-D ...integrated circuit (3DIC) system. We show a patterned growth of multiwalled CNTs on the substrate with prestructured bond pads including a complete metallization system for an electrical characterization. We succeeded in achieving reliable flip-chip connections between CNT-covered contact pads and metal pads during the room temperature bonding process. The goal is a reversible electrical and mechanical chip assembly with CNT bumps. Based on the current-voltage (<inline-formula> <tex-math notation="LaTeX">{I} </tex-math></inline-formula>-<inline-formula> <tex-math notation="LaTeX">{V} </tex-math></inline-formula>) measurements, the resistivity (<inline-formula> <tex-math notation="LaTeX">\rho </tex-math></inline-formula>) of the grown CNTs is found to be close to <inline-formula> <tex-math notation="LaTeX">\sim 10^{-{6}}\,\,{\sf \Omega }\text{m} </tex-math></inline-formula>. With the proposed 3DIC process flow, the vertically electrical connection between two different Si substrates is demonstrated successfully. The connection resistance in the full 3-D system is very promising (<inline-formula> <tex-math notation="LaTeX">\sim 2.43~{\sf \Omega } </tex-math></inline-formula>), compared with other's work (<inline-formula> <tex-math notation="LaTeX">\sim 12~{\sf \Omega } </tex-math></inline-formula>). The different bonding materials (In versus Sn) and bonding times are also investigated systemically and further optimized. This brief provides a useful solution for the future electrical connection in the high-performance and high-dense 3-D integrated devices.
Abstract
Stimuli-responsive behaviors of flexible metal–organic frameworks (MOFs) make these materials promising in a wide variety of applications such as gas separation, drug delivery, and molecular ...sensing. Considerable efforts have been made over the last decade to understand the structural changes of flexible MOFs in response to external stimuli. Uniform pore deformation has been used as the general description. However, recent advances in synthesizing MOFs with non-uniform porous structures, i.e. with multiple types of pores which vary in size, shape, and environment, challenge the adequacy of this description. Here, we demonstrate that the CO
2
-adsorption-stimulated structural change of a flexible MOF, ZIF-7, is induced by CO
2
migration in its non-uniform porous structure rather than by the proactive opening of one type of its guest-hosting pores. Structural dynamics induced by guest migration in non-uniform porous structures is rare among the enormous number of MOFs discovered and detailed characterization is very limited in the literature. The concept presented in this work provides new insights into MOF flexibility.
Numerous studies have examined the composition of and factors shaping the oral bacterial microbiota in healthy adults; however, similar studies on the less dominant yet ecologically and clinically ...important fungal microbiota are scarce. In this study, we characterized simultaneously the oral bacterial and fungal microbiomes in a large cohort of systemically healthy Chinese adults by sequencing the bacterial 16S rRNA gene and fungal internal transcribed spacer. We showed that different factors shaped the oral bacterial and fungal microbiomes in healthy adults. Sex and age were associated with the alpha diversity of the healthy oral bacterial microbiome but not that of the fungal microbiome. Age was also a major factor affecting the beta diversity of the oral bacterial microbiome; however, it only exerted a small effect on the oral fungal microbiome when compared with other variables. After controlling for age and sex, the bacterial microbiota structure was most affected by marital status, recent oral conditions and oral hygiene-related factors, whereas the fungal microbiota structure was most affected by education level, fruits and vegetables, and bleeding gums. Bacterial-fungal interactions were limited in the healthy oral microbiota, with the strongest association existing between Pseudomonas sp. and
. Several bacterial amplicon sequence variants (ASVs) belonging to Veillonella atypica and the genera
, Streptococcus and
and fungal ASVs belonging to Candida albicans and the genus
were revealed as putative pivotal members of the healthy oral microbiota. Overall, our study has facilitated understanding of the determining factors and cross-kingdom interactions of the healthy human oral microbiome.
Numerous studies have examined the bacterial community residing in our oral cavity; however, information on the less dominant yet ecologically and clinically important fungal members is limited. In this study, we characterized simultaneously the oral bacterial and fungal microbial communities in a large cohort of healthy Chinese adults, examined their associations with an array of host factors, and explored potential interactions between the two microbial groups. We showed that different factors shape the diversity and structure of the oral bacterial and fungal microbial communities in healthy adults, with, for instance, sex and age only associated with the diversity of the bacterial community but not that of the fungal community. Besides, we found that bacterial-fungal interactions are limited in the healthy oral cavity. Overall, our study has facilitated understanding of the determining factors and bacterial-fungal interactions of the healthy human oral microbial community.
To identify the association between the expression of lncRNA NEAT1 and clinicopathological characteristics of patients with HCC, and to explore the prognostic significance of lncRNA NEAT1 in ...predicting prognosis of HCC.
We retrospectively reviewed 86 patients with HCC (35 female, 51 male) managed in our institution between 2009 and 2014. The expression level of lncRNA NEAT1 was detected by real-time PCR. Prognostic factors were evaluated using Kaplan–Meier curves and Cox proportional hazards models.
For the entire cohort of 86 patients, we showed that the expression level of NEAT1 was significantly higher in HCC tissues compared with non-tumorous tissues and NEAT1 was increased obviously in the HCC cell lines including SMMC-7721, Huh-7 and Hep3B (P < 0.001). MTT assay showed that si-NEAT1 remarkably inhibited the cell proliferation in three HCC cell lines. Moreover, over-expression of lncRNA NEAT1 was closely related to liver cirrhosis (P = 0.026), microvascular invasion (MVI) (P = 0.023), and TNM stage (P = 0.017). After adjusting for competing risk factors, we identified that expression level of lncRNA NEAT1 was an independently risk factor associated with the prognosis of patients with HCC (P = 0.031).
In this study, we found NEAT1 expressed significantly higher in HCC tissues compared with non-tumorous tissues. Overexpression of lncRNA NEAT1 was an independently risk factor associated with the prognosis of patients with HCC.
Abstract
Understanding the sources of lunar water is crucial for studying the history of lunar evolution, as well as the interaction of solar wind with the Moon and other airless bodies. Recent ...orbital spectral observations revealed that the solar wind is a significant exogenous driver of lunar surficial hydration. However, the solar wind is shielded over a period of 3–5 days per month as the Moon passes through the Earth’s magnetosphere, during which a significant loss of hydration is expected. Here we report the temporal and spatial distribution of polar surficial OH/H
2
O abundance, using Chandrayaan-1 Moon Mineralogy Mapper (
M
3
) data, which covers the regions inside/outside the Earth’s magnetosphere. The data shows that polar surficial OH/H
2
O abundance increases with latitude, and that the probability of polar surficial OH/H
2
O abundance remains at the same level when in the solar wind and in the magnetosphere by controlling latitude, composition, and lunar local time. This indicates that the OH/H
2
O abundance in the polar regions may be saturated, or supplemented from other possible sources, such as Earth wind (particles from the magnetosphere, distinct from the solar wind), which may compensate for thermal diffusion losses while the Moon lies within the Earth’s magnetosphere. This work provides some clues for studies of planet–moon systems, whereby the planetary wind serves as a bridge connecting the planet with its moons.
Understanding structural responses of metal–organic frameworks (MOFs) to external stimuli such as the inclusion of guest molecules and temperature/pressure has gained increasing attention in many ...applications, for example, manipulation and manifesto smart materials for gas storage, energy storage, controlled drug delivery, tunable mechanical properties, and molecular sensing, to name but a few. Herein, neutron and synchrotron diffractions along with Rietveld refinement and density functional theory calculations have been used to elucidate the responsive adsorption behaviors of defect-rich Zr-based MOFs upon the progressive incorporation of ammonia (NH3) and variable temperature. UiO-67 and UiO-bpydc containing biphenyl dicarboxylate and bipyridine dicarboxylate linkers, respectively, were selected, and the results establish the paramount influence of the functional linkers on their NH3 affinity, which leads to stimulus-tailoring properties such as gate-controlled porosity by dynamic linker flipping, disorder, and structural rigidity. Despite their structural similarities, we show for the first time the dramatic alteration of NH3 adsorption profiles when the phenyl groups are replaced by the bipyridine in the organic linker. These molecular controls stem from controlling the degree of H-bonding networks/distortions between the bipyridine scaffold and the adsorbed NH3 without significant change in pore volume and unit cell parameters. Temperature-dependent neutron diffraction also reveals the NH3-induced rotational motions of the organic linkers. We also demonstrate that the degree of structural flexibility of the functional linkers can critically be affected by the type and quantity of the small guest molecules. This strikes a delicate control in material properties at the molecular level.
Pier scour has been extensively studied in laboratory experiments. However, scour depth relationships based on data at the laboratory scale often yield unacceptable results when extended to field ...conditions. In this study, non-uniform gravel bed laboratory and field datasets with gravel of median size ranging from 2.7 to 14.25 mm were considered to predict the maximum equilibrium scour depth at cylindrical piers. Specifically, a total of 217 datasets were collected: 132 from literature sources and 85 in this study using new experiments at the laboratory scale, which constitute a novel contribution provided by this paper. From the analysis of data, it was observed that Melville and Coleman’s equation performs well in the case of laboratory datasets, while it tends to overestimate field measurements. Guo’s and Kim et al.’s relationships showed good agreements only for laboratory datasets with finer non-uniform sediments: deviations in predicting the maximum scour depth with non-uniform gravel beds were found to be significantly greater than those for non-uniform sand and fine gravel beds. Consequently, new K-factors for the Melville and Coleman’s equation were proposed in this study for non-uniform gravel-bed streams using a curve-fitting method. The results revealed good agreements between observations and predictions, where this might be an attractive advancement in overcoming scale effects. Moreover, a sensitivity analysis was performed to identify the most sensitive K-factors.
Climate models struggle to accurately represent the highly reflective boundary layer clouds overlying the remote and stormy Southern Ocean. We use in situ aircraft observations from the Southern ...Ocean Clouds, Radiation and Aerosol Transport Experimental Study (SOCRATES) to evaluate Southern Ocean clouds in a cloud‐resolving large‐eddy simulation (LES) and two coarse resolution global atmospheric models, the CESM Community Atmosphere Model (CAM6) and the GFDL Atmosphere Model (AM4), run in a nudged hindcast framework. We develop six case studies from SOCRATES data which span the range of observed cloud and boundary layer properties. For each case, the LES is run once forced purely using reanalysis data (fifth generation European Centre for Medium‐Range Weather Forecasts atmospheric reanalysis, “ERA5 based”) and once strongly nudged to an aircraft profile(“Obs based”). The ERA5‐based LES can be compared with the global models, which are also nudged to reanalysis data and are better for simulating cumulus. The Obs‐based LES closely matches an observed cloud profile and is useful for microphysical comparisons and sensitivity tests and simulating multilayer stratiform clouds. We use two‐moment Morrison microphysics in the LES and find that it simulates too few frozen particles in clouds occurring within the Hallett‐Mossop temperature range. We tweak the Hallett‐Mossop parameterization so that it activates within boundary layer clouds, and we achieve better agreement between observed and simulated microphysics. The nudged global climate models (GCMs) simulate liquid‐dominated mixed‐phase clouds in the stratiform cases but excessively glaciate cumulus clouds. Both GCMs struggle to represent two‐layer clouds, and CAM6 has low droplet concentrations in all cases and underpredicts stratiform cloud‐driven turbulence.
Plain Language Summary
The Southern Ocean, the wide band of water North of Antarctica, is the stormiest place on Earth. Weather systems constantly whirl the atmosphere and blanket the ocean in clouds. Low‐lying clouds reflect sunlight back to space and cool the Earth. Here, we investigate how well the computer models that we use to understand the climate and to forecast future climates can simulate these clouds. We use recent aircraft measurements from the Southern Ocean Clouds, Radiation and Aerosol Transport Experimental Study (SOCRATES) to evaluate two leading U.S. global climate models, the GFDL Atmosphere Model (AM4) and the CESM Community Atmosphere Model (CAM6). We additionally run detailed simulations of Southern Ocean clouds over a small area to understand which physical processes are relevant to cloud formation. We find that our detailed simulations include most of the physics that is relevant to low‐lying Southern Ocean clouds, but one particular type of ice multiplication process, called Hallett‐Mossop rime splintering, is not active enough. CAM6 and AM4 make too much ice in, or glaciate, cumulus clouds. CAM6 has too few cloud droplets, and we hypothesize that this is caused by glaciation and by the simulated clouds driving too little turbulent mixing of the atmosphere.
Key Points
SAM LES represents diverse Southern Ocean boundary layer and cloud structures well
CAM6 and AM4 maintain supercooled water in stratiform clouds but excessively glaciate cumuli
CAM6 underpredicts stratiform cloud‐driven turbulence and cloud droplet concentration
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