"Matching Rule" for Generation, Modulation and Amplification of Circularly Polarized Luminescence.

ConspectusCircularly polarized luminescence (CPL) generated by chiral luminescent systems has sparked enormous attention in multidisciplinary field as it brings infinite potential for applications, such as 3D optical displays, biological probes, and chiroptical sensors. Satisfying both the conditions of chirality and luminescence (including fluorescence or phosphorescence) is a prerequisite for constructing CPL materials. In this regard, whether in organic, inorganic, or hybrid systems, chiral and luminescent components generally involve effective coupling through covalent or noncovalent bonds. For covalent interactions, such as the copolymerization of chiral and luminescent monomers, although covalent bonds provide high stability for the system, they inevitably involve tedious preparation procedures that connect chirality and luminescence together. For noncovalent bonds, take supramolecular assembly as an example, chiral elements and achiral light-emitting units are chiral transferred through intermolecular interactions, and their advantages include the diversity of luminescent and chiral building blocks, the stimuli responsiveness brought by noncovalent bonds, as well as the potential amplification of CPL signals by coassembly. However, the stability of the assembly system may be poor, and the assembly chiroptical performance and morphology are difficult to predict. Gratifyingly, matching rule that do not rely on covalent together with noncovalent interactions allows for the effortless construction, modulation, as well as amplification of CPL systems.In this Account, we overview different strategies based on matching rule, including fluorescence-selective absorption, circularly polarized reflection, and circularly polarized fluorescence energy transfer (CPF-ET). Examples of these strategies are illustrated with a focus on helical polymers in light of their appealing structures and wide uses. For instance, for fluorescence-selective absorption, chiral helical polymers can convert racemic fluorescence light into a circularly polarized one with specific handedness by simply overlapping the helical polymer's circular dichroism (CD) spectra with the luminophore's emission spectra. For circularly polarized reflection, employing the selective reflection of certain handedness's circularly polarized light, the high helical twisting power (HTP) of the helical polymer in the cholesteric liquid crystals (N*-LCs) gives the system high glum. Additionally, for CPF-ET, only the emission spectrum of the donor and the absorption (or excitation) spectrum of the achiral acceptor are required to overlap, and no covalent or noncovalent interactions between the two are required. An outlook for the CPL materials related to matching rule which will avail the optimization and extension of this intriguing approach concludes the Account. We hope that the Account will offer insightful inspiration for the flourishing progress of chiroptical systems and present exciting opportunities.

Circularly polarized luminescence in quantum dot-based materials.

Quantum dots (QDs) have emerged as fantastic luminescent nanomaterials with significant potential due to their unique photoluminescence properties. With the rapid development of circularly polarized luminescence (CPL) materials, many researchers have associated QDs with the CPL property, resulting in numerous novel CPL-active QD-containing materials in recent years. The present work reviews the latest advances in CPL-active QD-based materials, which are classified based on the types of QDs, including perovskite QDs, carbon dots, and colloidal semiconductor QDs. The applications of CPL-active QD-based materials in biological, optoelectronic, and anti-counterfeiting fields are also discussed. Additionally, the current challenges and future perspectives in this field are summarized. This review article is expected to stimulate more unprecedented achievements based on CPL-active QD-based materials, thus further promoting their future practical applications.

Event-Triggered Multiasynchronous H∞ Control for Markov Jump Systems With Transmission Delay.

In this article, the issue of event-triggered multiasynchronous H∞ control for Markov jump systems with transmission delay is concerned. In order to reduce sampling frequency, multiple event-triggered schemes (ETSs) are introduced. Then hidden Markov model (HMM) is employed to describe multiasynchronous jumps among subsystems, ETSs, and controller. Based on the HMM, the time-delay closed-loop model is constructed. In particular, when triggered data are transmitted over networks, a large transmission delay may cause disorder of transmission data such that the time-delay closed-loop model cannot be developed directly. To overcome this difficulty, a packet loss schedule is presented and the unified time-delay closed-loop system is obtained. By the use of the Lyapunov-Krasovskii functional method, sufficient conditions with the controller design are formulated for guaranteeing the H∞ performance of the time-delay closed-loop system. Finally, the effectiveness of the proposed control strategy is demonstrated by two numerical examples.

Normal reference values for magnetic resonance imaging measurements of the fetal internal jugular veins in middle and late pregnancy.

BACKGROUND: At present, there is a lack of normal magnetic resonance imaging (MRI) morphometric reference values for fetal internal jugular veins during middle and late pregnancy. OBJECTIVE: We used MRI to assess the morphology and cross-sectional area of the internal jugular veins of fetuses during middle and late pregnancy and to explore the clinical value of these parameters. MATERIALS AND METHODS: The MRI images of 126 fetuses in middle and late pregnancy were retrospectively analysed to determine the optimal sequence for imaging the internal jugular veins. Morphological observation of the fetal internal jugular veins in each gestational week was carried out, lumen cross-sectional area was measured and the relationship between these data and gestational age was analysed. RESULTS: The balanced steady-state free precession sequence was superior to other MRI sequences used for fetal imaging. The cross section of fetal internal jugular veins was predominantly circular in both the middle and late stages of pregnancy, however the prevalence of an oval cross section was significantly higher in the late gestational age group. The cross-sectional area of the lumen of the fetal internal jugular veins increased with increasing gestational age. Fetal jugular vein asymmetry was common, with the right jugular vein being dominant in the high gestational age group. CONCLUSION: We provide normal reference values for fetal internal jugular veins measured by MRI. These values may form the basis for clinical assessment of abnormal dilation or stenosis.

Adaptive Neural Event-Triggered Control of Networked Markov Jump Systems Under Hybrid Cyberattacks.

This article is concerned with the neural network (NN)-based event-triggered control problem for discrete-time networked Markov jump systems with hybrid cyberattacks and unmeasured states. The event-triggered mechanism (ETM) is used to reduce the communication load, and a Luenberger observer is introduced to estimate the unmeasured states. Two kinds of cyberattacks, denial-of-service (DoS) attacks and deception attacks, are investigated due to the vulnerability of cyberlayer. For the sake of mitigating the impact of these two types of cyberattacks on system performance, the ETM under DoS jamming attacks is discussed first, and a new estimation of such mechanism is given. Then, the NN technique is applied to approximate the injected false information. Some sufficient conditions are derived to guarantee the boundedness of the closed-loop system, and the observer and controller gains are presented by solving a set of matrix inequalities. The effectiveness of the presented control method is demonstrated by a numerical example.

Event-Triggered and Self-Triggered L∞ Control for Markov Jump Stochastic Nonlinear Systems Under DoS Attacks.

This article investigates event-triggered and self-triggered L∞ control problems for the Markov jump stochastic nonlinear systems subject to denial-of-service (DoS) attacks. When attacks prevent system devices from obtaining valid information over networks, a new switched model with unstable subsystems is constructed to characterize the effect of DoS attacks. On the basis of the switched model, a multiple Lyapunov function method is utilized and a set of sufficient conditions incorporating the event-triggering scheme (ETS) and restriction of DoS attacks are provided to preserve L∞ performance. In particular, considering that ETS based on mathematical expectation is difficult to be implemented on a practical platform, a self-triggering scheme (STS) without mathematical expectation is presented. Meanwhile, to avoid the Zeno behavior resulted from general exogenous disturbance, a positive lower bound is fixed in STS in advance. In addition, the exponent parameters are designed in STS to reduce triggering frequency. Based on the STS, the mean-square asymptotical stability and almost sure exponential stability are both discussed when the system is in the absence of exogenous disturbance. Finally, two examples are given to substantiate the effectiveness of the proposed method.

Adaptive Neural State Estimation of Markov Jump Systems Under Scheduling Protocols and Probabilistic Deception Attacks.

The neural-network (NN)-based state estimation issue of Markov jump systems (MJSs) subject to communication protocols and deception attacks is addressed in this article. For relieving communication burden and preventing possible data collisions, two types of scheduling protocols, namely: 1) the Round-Robin (RR) protocol and 2) weighted try-once-discard (WTOD) protocol, are applied, respectively, to coordinate the transmission sequence. In addition, considering that the communication channel may suffer from mode-dependent probabilistic deception attacks, a hidden Markov-like model is proposed to characterize the relationship between the malicious signal and system mode. Then, a novel adaptive neural state estimator is presented to reconstruct the system states. By taking the influence of deception attacks into performance analysis, sufficient conditions under two different scheduling protocols are derived, respectively, so as to ensure the ultimately boundedness of the estimate error. In the end, simulation results testify the correctness of the adaptive neural estimator design method proposed in this article.

Event-Triggered Resilient L∞ Control for Markov Jump Systems Subject to Denial-of-Service Jamming Attacks.

In this article, the event-triggered resilient L∞ control problem is concerned for the Markov jump systems in the presence of denial-of-service (DoS) jamming attacks. First, a fixed lower bound-based event-triggering scheme (ETS) is presented in order to avoid the Zeno problem caused by exogenous disturbance. Second, when DoS jamming attacks are involved, the transmitted data are blocked and the old control input is kept by using the zero-order holder (ZOH). On the basis of this process, the effect of DoS attacks on ETS is further discussed. Next, by utilizing the state-feedback controller and multiple Lyapunov functions method, some criteria incorporating the restriction of DoS jamming attacks are proposed to guarantee the L∞ control performance of the event-triggered Markov closed-loop jump system. In particular, the bounded transition rates rather than the exact ones are taken into account. That is appropriate for the practical environment in which transition rates of the Markov process are difficult to measure accurately. Correspondingly, some criteria are proposed to obtain state-feedback gains and event-triggering parameters simultaneously. Finally, we provide two examples to show the effectiveness of the proposed method.

Chiral Helical Polymer/Perovskite Hybrid Nanofibers with Intense Circularly Polarized Luminescence.

Chiral perovskites with circularly polarized luminescence (CPL) performance have attracted tremendous attention. This contribution reports a convenient and universal strategy for constructing chiral helical polymer/perovskite hybrid nanofibers with outstanding CPL properties. The hybrid nanofibers are prepared through a one-step electrospinning method in which chiral helical polyacetylenes, perovskite nanocrystals, and polyacrylonitrile serve as a handed-selective fluorescence filter, fluorescent source, and electrospinning matrix, respectively. Specially, perovskite nanocrystals are in situ formed during the electrospinning process, which avoids the tedious process for preparing and purifying perovskites. The prepared hybrid nanofibers all exhibit good long-time stability in air, owing to the effective protection effect of polymer matrix. More importantly, intense CPL emissions with high dissymmetry factor up to 10-2 level are obtained in the hybrid nanofibers. Furthermore, the emission color of CPL can be easily tuned by adjusting the precursors of perovskites. This work provides an efficient technique toward various kinds of CPL-active perovskite nanomaterials for both scientific research and future practical applications.

Mussel byssus cuticle-inspired ultrastiff and stretchable triple-crosslinked hydrogels.

Applications in the harsh environment require hydrogels with ultra-stiffness, toughness, and stretchability. However, it remains a challenge to increase the elastic modulus without sacrificing the maximum elongation of hydrogels, because of the trade-off between stiffness and extensibility. Inspired by the crosslinking hierarchy of mussel byssus cuticle, here, we report a strategy to fabricate an ultra-stiff, tough and stretchable triple-crosslinked (TC) hydrogel. The polymer is crosslinked by chemical crosslinker at first, subsequently by introducing a polyphenolic compound, tannic acid (TA), and metal ions. The hydrogen-bond-based network between the polymer and TA works as an extensible and energy-dissipative network, mimicking the matrix of the cuticle, while the higher crosslinked domains formed by the coordinate bonds between TA and metal ions contribute to the stiffness. The triple-crosslinked hydrogel exhibits two orders of magnitude increase in stiffness (E = 58 MPa), but without sacrificing the maximum elongation (ε = 850%), compared with those of metal-free hydrogels (E = 0.18 MPa, and ε = 860%). The combination of ultra-stiffness, toughness, and stretchability in hydrogels is successfully achieved through leveraging the hierarchically cross-linked network based on hydrogen bonding and coordination bonding. Moreover, utilizing the wide distribution of bonding strength of coordination interaction, the mechanical properties of triple-crosslinked hydrogels can be manipulated by using different kinds of catechol-metal coordination.

Non-3d Metal Modulation of a 2D Ni-Co Heterostructure Array as Multifunctional Electrocatalyst for Portable Overall Water Splitting.

Portable water splitting devices driven by rechargeable metal-air batteries or solar cells are promising, however, their scalable usages are still hindered by lack of suitable multifunctional electrocatalysts. Here, a highly efficient multifunctional electrocatalyst is demonstrated, i.e., 2D nanosheet array of Mo-doped NiCo2 O4 /Co5.47 N heterostructure deposited on nickel foam (Mo-NiCo2 O4 /Co5.47 N/NF). The successful doping of non-3d high-valence metal into a heterostructured nanosheet array, which is directly grown on a conductive substrate endows the resultant catalyst with balanced electronic structure, highly exposed active sites, and binder-free electrode architecture. As a result, the Mo-NiCo2 O4 /Co5.47 N/NF exhibits remarkable catalytic activity toward the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER), affording high current densities of 50 mA cm-2 at low overpotentials of 310 mV for OER, and 170 mV for HER, respectively. Moreover, a low voltage of 1.56 V is achieved for the Mo-NiCo2 O4 /Co5.47 N/NF-based water splitting cell to reach 10 mA cm-2 . More importantly, a portable overall water splitting device is demonstrated through the integration of a water-splitting cell and two Zn-air batteries (open-circuit voltage of 1.43 V), which are all fabricated based on Mo-NiCo2 O4 /Co5.47 N/NF, demonstrating a low-cost way to generate fuel energy. This work offers an effective strategy to develop high-performance metal-doped heterostructured electrode.

MnO2 Nanosheet-Assembled Hollow Polyhedron Grown on Carbon Cloth for Flexible Aqueous Zinc-Ion Batteries.

Aqueous zinc-ion batteries (ZIBs) have been considered as prospective alternatives for lithium-ion batteries, which are able to serve as power sources for next-generation wearable and flexible devices, owing to the merits of abundant zinc resources and high safety of aqueous electrolyte. However, the lack of suitable cathode materials with flexibility for ZIBs hinders their further application. Herein, a novel cathode material [i.e., MnO2 nanosheet-assembled hollow polyhedron anchored on carbon cloth (MnO2 /CC)] was prepared through a rapid hydrothermal method by using ZIF-67 as self-sacrificing template. When tested in an aqueous ZIB, the MnO2 /CC delivered a high reversible capacity of 263.9 mAh g-1 at 1.0 A g-1 after 300 cycles, far exceeding those of the commercial MnO2 electrode. More importantly, benefiting from the unique structural advantages, a flexible ZIB assembled based on the MnO2 /CC displayed a stable output voltage of 1.53 V and a specific capacity of 91.7 mAh g-1 at 0.1 A g-1 after 30 cycles. It also successfully lit LED bulbs even under different bending angles, showing good flexibility. This research contributes to the development of MnO2 -based cathode materials for high-performance flexible ZIBs.

Pt-Cu Bimetallic Nanoparticles Loaded in the Lumen of Halloysite Nanotubes.

In this study, we demonstrate that Pt-Cu bimetallic nanoparticles with different compositions (Pt3Cu, PtCu, PtCu3) can be loaded in the lumen of halloysite nanotube (HNT) via a simple one-pot reduction. Increasing the pH of metallic precursor (H2PtCl6 and CuCl2)/HNT solutions enhances the dissociation of H2PtCl6, advancing the association of [PtCl6]2- with the positively charged inner surface (Al-OH) of HNT. Moreover, the shrinkage of bond length from Pt-Cl in [PtCl6]2- to Pt-O in [PtCl4(OH)2]2- due to pH-modulated ligand exchange may also assist Pt(IV) being trapped inside the halloysite. In the meantime, Cu(II) cations may complex with Pt(IV) anions via electrostatic force that would help the formation of Pt-Cu bimetallic nanoparticles inside the halloysite. The obtained PtCu3@HNT system shows a significantly enhanced catalytic performance in the reduction of 4-nitrophenol by sodium borohydride, with a mass activity approximating 60 times higher than that of unloaded Pt nanoparticles. The high catalytic efficiency can be maintained after thermal treatment at 200 or 400 °C.

A Tumor-Localized Approach to Bypass Anti-4-1BB Immuno-Toxicity.

4-1BB (CD137) is an important costimulatory molecule upregulated on antigen-experienced T cells, however, clinical development of 4-1BB agonists has stalled because of significant liver immuno-toxicity. Using rational protein engineering, a next-generation anticalin-antibody-based therapy achieved localized 4-1BB activation triggered by tumor-expressed antigen, helping to revitalize this pathway in immuno-oncology.See related article by Hinner et al., p. 5878.

The combination of metal-organic frameworks and polydopamine nanotubes aiming for efficient one-dimensional oxygen reduction electrocatalyst.

Metal organic frameworks (MOFs) derived carbon nanomaterial is among the most promising electrocatalysts as it has high surface area and plentiful doping elements. A further improvement in their performance is focusing on its diffusion-limited microporous nanostructure and the relatively poor graphitic degree. Herein, a novel 1D Co/N co-doped carbon nanomaterial (Co/N-CNT) with hierarchical micro- and mesoporous structure is prepared via epitaxial growth of ZIF-67 nanocrystals on polydopamine nanotubes (PDA NTs), followed by pyrolysis and acid leaching. Thanks to the inherent nature of PDA NTs, ZIF-67 nanocrystals were restrictedly grown on their surface homogeneously. After further treatment, the ZIF-67 derived Co/N doped carbon layers not only protect the integrity of 1D structure, but also exhibit "niches" like mesoporous structure to expose more active sites toward boosting oxygen reduction reaction. The rational designed Co/N-CNT composites have a comparable ORR activity to the commercial Pt/C catalyst, superior methanol tolerance and long-time durability in alkaline media, which may shed light on their further application toward energy conversion and storage.

Single small molecule-assembled nanoparticles mediate efficient oral drug delivery.

Oral drug delivery, which requires surviving the harsh environment in the gastrointestinal (GI) tract and penetrating the intestinal epithelium, has not been achieved using simple formulation nanoparticles (NPs). Medicinal natural products (MNPs) have been widely used in traditional medicine for disease management through oral consumption. However, most pharmacologically active compounds within MNPs do not have the properties suitable for oral applications. We hypothesize that some MNPs contain natural nanomaterials that can convert those compounds into oral formulations by forming NPs. After screening 66 MNPs, we identified five classes of small molecules that form NPs, many of which are capable of efficient drug encapsulation and GI penetration. We show that one of them, dehydrotrametenolic acid (DTA), is capable of mediating oral delivery for effective disease treatment. We determine that DTA NPs assemble through hydrogen bonding and penetrate the GI tract via apical sodium-dependent bile acid transporter. Our study reveals a novel class of single component, small molecule- assembled NPs for oral drug delivery, and suggests a novel approach to modernizing MNPs through nanomaterial discovery.

Short- and long-term outcomes of laparoscopic surgery in elderly patients with rectal cancer.

PURPOSE: This study aimed to use propensity score matching (PSM) to compare the short- and long-term outcomes of laparoscopic surgery for the treatment of rectal cancer in elderly and middle-aged patients. METHODS: Data were retrospectively obtained from 588 patients aged ≥60 years when they underwent laparoscopic surgery for rectal cancer in our hospital between January 2009 and December 2016. The patients were divided into an elderly group (≥70 years) or a middle-aged group (60-69 years), and were subsequently matched 1:1 using PSM for sex, body mass index, Charlson comorbidity index (CCI), tumor location, clinical stage, and American Society of Anesthesiologists (ASA) score. A total of 115 patients from each group were matched and included in the study, and their short-term and long-term outcomes were compared. RESULTS: The elderly group had greater intraoperative blood loss and a higher surgical conversion rate, although the other outcomes were similar between the two groups (surgical time, pathology results, 30-day incidence of complications, and incidence of major complications). No patients died intraoperatively or within 30 days after surgery. There were no significant differences in the two groups' rates of tumor recurrence, 5-year overall survival, and 5-year disease-free survival. CONCLUSION: Although elderly patients had greater intraoperative blood loss and a higher surgical conversion rate, laparoscopic surgery for rectal cancer provided similar short-term and long-term outcomes among middle-aged and elderly patients.

The JAZF1-SUZ12 fusion protein disrupts PRC2 complexes and impairs chromatin repression during human endometrial stromal tumorogenesis.

The Polycomb repressive complex 2 (PRC2), which contains three core proteins EZH2, EED and SUZ12, controls chromatin compaction and transcription repression through trimethylation of lysine 27 on histone 3. The (7;17)(p15;q21) chromosomal translocation present in most cases of endometrial stromal sarcomas (ESSs) results in the in-frame fusion of the JAZF1 and SUZ12 genes. We have investigated whether and how the fusion protein JAZF1-SUZ12 functionally alters PRC2. We found that the fusion protein exists at high levels in ESS containing the t(7;17). Co-transient transfection assay indicated JAZF1-SUZ12 destabilized PRC2 components EZH2 and EED, resulting in decreased histone methyl transferase (HMT) activity, which was confirmed by in vitro studies using reconstituted PRC2 and nucleosome array substrates. We also demonstrated the PRC2 containing the fusion protein decreased the binding affinity to target chromatin loci. In addition, we found that trimethylation of H3K27 was decreased in ESS samples with the t(7;17), but there was no detectable change in H3K9 in these tissues. Moreover, re-expression of SUZ12 in Suz12 (-/-) ES cells rescued the neuronal differentiation while the fusion protein failed to restore this function and enhanced cell proliferation. In summary, our studies reveal that JAZF1-SUZ12 fusion protein disrupts the PRC2 complex, abolishes HMT activity and subsequently activates chromatin/genes normally repressed by PRC2. Such dyesfunction of PRC2 inhibits normal neural differentiation of ES cell and increases cell proliferation. Related changes induced by the JAZF-SUZ12 protein in endometrial stromal cells may explain the oncogenic effect of the t(7;17) in ESS.

Effect of hydrodynamic cavitation in the tissue erosion by pulsed high-intensity focused ultrasound (pHIFU).

High-intensity focused ultrasound (HIFU) is emerging as an effective therapeutic modality in clinics. Besides the thermal ablation, tissue disintegration is also possible because of the interaction between the distorted HIFU bursts and either bubble cloud or boiling bubble. Hydrodynamic cavitation is another type of cavitation and has been employed widely in industry, but its role in mechanical erosion to tissue is not clearly known. In this study, the bubble dynamics immediately after the termination of HIFU exposure in the transparent gel phantom was captured by high-speed photography, from which the bubble displacement towards the transducer and the changes of bubble size was quantitatively determined. The characteristics of hydrodynamic cavitation due to the release of the acoustic radiation force and relaxation of compressed surrounding medium were found to associate with the number of pulses delivered and HIFU parameters (i.e. pulse duration and pulse repetition frequency). Because of the initial big bubble (~1 mm), large bubble expansion (up to 1.76 folds), and quick bubble motion (up to ~1 m s-1) hydrodynamic cavitation is significant after HIFU exposure and may lead to mechanical erosion. The shielding effect of residual tiny bubbles would reduce the acoustic energy delivered to the pre-existing bubble at the focus and, subsequently, the hydrodynamic cavitation effect. Tadpole shape of mechanical erosion in ex vivo porcine kidney samples was similar to the contour of bubble dynamics in the gel. Liquefied tissue was observed to emit towards the transducer through the punctured tissue after HIFU exposure in the sonography. In summary, the release of HIFU exposure-induced hydrodynamic cavitation produces significant bubble expansion and motion, which may be another important mechanism of tissue erosion. Understanding its mechanism and optimizing the outcome would broaden and enhance HIFU applications.

Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging.

The blood-brain barrier (BBB) is partially disrupted in brain tumors. Despite the gaps in the BBB, there is an inadequate amount of pharmacological agents delivered into the brain. Thus, the low delivery efficiency renders many of these agents ineffective in treating brain cancer. In this report, we proposed an "autocatalytic" approach for increasing the transport of nanoparticles into the brain. In this strategy, a small number of nanoparticles enter into the brain via transcytosis or through the BBB gaps. After penetrating the BBB, the nanoparticles release BBB modulators, which enables more nanoparticles to be transported, creating a positive feedback loop for increased delivery. Specifically, we demonstrated that these autocatalytic brain tumor-targeting poly(amine-co-ester) terpolymer nanoparticles (ABTT NPs) can readily cross the BBB and preferentially accumulate in brain tumors at a concentration of 4.3- and 94.0-fold greater than that in the liver and in brain regions without tumors, respectively. We further demonstrated that ABTT NPs were capable of mediating brain cancer gene therapy and chemotherapy. Our results suggest ABTT NPs can prime the brain to increase the systemic delivery of therapeutics for treating brain malignancies.