High-Grade Pleomorphic Sarcomas Treated with Immune Checkpoint Blockade: The MD Anderson Cancer Center Experience.

BACKGROUND: Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas. Few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and other high-grade pleomorphic STS patients are available. PURPOSE: The purpose of our study is to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution. METHODS: This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023. Patients included in trials for which results are not yet published were excluded. RESULTS: Thirty-six patients with advanced/metastatic pleomorphic sarcomas were included. The median age was 52 years. A total of 26 patients (72%) had UPSs and 10 patients (28%) had other high-grade pleomorphic sarcomas. The median follow-up time was 8.8 months. The median PFS was 2.9 months. The 3-month PFS and 6-month PFS were 46% and 32%, respectively. The median OS was 12.9 months. The 12-month OS and 24-month OS were 53% and 29%, respectively. The best response, previous RT, and type of ICB treatment were significantly and independently associated with shorter PFS (p = 0.0012, p = 0.0019 and p = 0.036, respectively). No new safety signal was identified, and the toxicity was overall manageable with no toxic deaths and only four patients (11%) stopping treatment due to toxicity. CONCLUSIONS: Real-world retrospective data are consistent with the published literature, with a promising 6-month PFS of 32%. Partial or stable responders to ICB treatment have significantly improved PFS compared to progressors.

2D Covalent Organic Framework Membranes for Liquid-Phase Molecular Separations: State of the Field, Common Pitfalls, and Future Opportunities.

2D covalent organic frameworks (2D COFs) are attractive candidates for next-generation membranes due to their robust linkages and uniform, tunable pores. Many publications have claimed to achieve selective molecular transport through COF pores, but reported performance metrics for similar networks vary dramatically, and in several cases the reported experiments are inadequate to support such conclusions. These issues require a reevaluation of the literature. Published examples of 2D COF membranes for liquid-phase separations can be broadly divided into two categories, each with common performance characteristics: polycrystalline COF films (most >1 µm thick) and weakly crystalline or amorphous films (most <500 nm thick). Neither category has demonstrated consistent relationships between the designed COF pore structure and separation performance, suggesting that these imperfect materials do not sieve molecules through uniform pores. In this perspective, rigorous practices for evaluating COF membrane structures and separation performance are described, which will facilitate their development toward molecularly precise membranes capable of performing previously unrealized chemical separations. In the absence of this more rigorous standard of proof, reports of COF-based membranes should be treated with skepticism. As methods to control 2D polymerization improve, precise 2D polymer membranes may exhibit exquisite and energy efficient performance relevant for contemporary separation challenges.

SABR for Sarcoma Lung Metastases: Indications for Treatment and Guidance for Patient Selection.

PURPOSE: The lungs are the most common site of metastasis for patients with soft tissue sarcoma. SABR is commonly employed to treat lung metastases among select patients with sarcoma with limited disease burden. We sought to evaluate outcomes and patterns of failure among patients with sarcoma treated with SABR for their lung metastases. METHODS AND MATERIALS: We performed a retrospective review of patients treated at a tertiary cancer center between 2006 and 2020. Patient disease status at the time of SABR was categorized as either oligorecurrent or oligoprogressive. The Kaplan-Meier method was used to estimate disease outcomes. Uni- and multivariable analyses were conducted using the Cox proportional hazards model. RESULTS: We identified 70 patients with soft tissue sarcoma treated with SABR to 98 metastatic lung lesions. Local recurrence-free survival after SABR treatment was 83% at 2 years. On univariable analysis, receipt of comprehensive SABR to all sites of pulmonary metastatic disease at the time of treatment was associated with improved progression-free survival (PFS; hazard ratio [HR], 0.51 [0.29-0.88]; P = .02). On multivariable analysis, only having systemic disease controlled at the time of SABR predicted improved PFS (median PFS, 14 vs 4 months; HR, 0.37 [0.20-0.69]; P = .002) and overall survival (median overall survival, 51 vs 14 months; HR, 0.17 [0.08-0.35]; P < .0001). CONCLUSIONS: SABR provides durable long-term local control for sarcoma lung metastases. The most important predictor for improved outcomes was systemic disease control. Careful consideration of these factors should help guide decisions in a multidisciplinary setting to appropriately select the optimal candidates for SABR.

Hydrophobic polyamide nanofilms provide rapid transport for crude oil separation.

Hydrocarbon separation relies on energy-intensive distillation. Membrane technology can offer an energy-efficient alternative but requires selective differentiation of crude oil molecules with rapid liquid transport. We synthesized multiblock oligomer amines, which comprised a central amine segment with two hydrophobic oligomer blocks, and used them to fabricate hydrophobic polyamide nanofilms by interfacial polymerization from self-assembled vesicles. These polyamide nanofilms provide transport of hydrophobic liquids more than 100 times faster than that of conventional hydrophilic counterparts. In the fractionation of light crude oil, manipulation of the film thickness down to ~10 nanometers achieves permeance one order of magnitude higher than that of current state-of-the-art hydrophobic membranes while retaining comparable size- and class-based separation. This high permeance can markedly reduce plant footprint, which expands the potential for using membranes made of ultrathin nanofilms in crude oil fractionation.

Aligned macrocycle pores in ultrathin films for accurate molecular sieving.

Polymer membranes are widely used in separation processes including desalination1, organic solvent nanofiltration2,3 and crude oil fractionation4,5. Nevertheless, direct evidence of subnanometre pores and a feasible method of manipulating their size is still challenging because of the molecular fluctuations of poorly defined voids in polymers6. Macrocycles with intrinsic cavities could potentially tackle this challenge. However, unfunctionalized macrocycles with indistinguishable reactivities tend towards disordered packing in films hundreds of nanometres thick7-9, hindering cavity interconnection and formation of through-pores. Here, we synthesized selectively functionalized macrocycles with differentiated reactivities that preferentially aligned to create well-defined pores across an ultrathin nanofilm. The ordered structure was enhanced by reducing the nanofilm thickness down to several nanometres. This orientated architecture enabled direct visualization of subnanometre macrocycle pores in the nanofilm surfaces, with the size tailored to ångström precision by varying the macrocycle identity. Aligned macrocycle membranes provided twice the methanol permeance and higher selectivity compared to disordered counterparts. Used in high-value separations, exemplified here by enriching cannabidiol oil, they achieved one order of magnitude faster ethanol transport and threefold higher enrichment than commercial state-of-the-art membranes. This approach offers a feasible strategy for creating subnanometre channels in polymer membranes, and demonstrates their potential for accurate molecular separations.

Multimodal confined water dynamics in reverse osmosis polyamide membranes.

While polyamide (PA) membranes are widespread in water purification and desalination by reverse osmosis, a molecular-level understanding of the dynamics of both confined water and polymer matrix remains elusive. Despite the dense hierarchical structure of PA membranes formed by interfacial polymerization, previous studies suggest that water diffusion remains largely unchanged with respect to bulk water. Here, we employ neutron spectroscopy to investigate PA membranes under precise hydration conditions, and a series of isotopic contrasts, to elucidate water transport and polymer relaxation, spanning ps-ns timescales, and Å-nm lengthscales. We experimentally resolve, for the first time, the multimodal diffusive nature of water in PA membranes: in addition to (slowed down) translational jump-diffusion, we observe a long-range and a localized mode, whose geometry and timescales we quantify. The PA matrix is also found to exhibit rotational relaxations commensurate with the nanoscale confinement observed in water diffusion. This comprehensive 'diffusion map' can anchor molecular and nanoscale simulations, and enable the predictive design of PA membranes with tuneable performance.

A smart and responsive crystalline porous organic cage membrane with switchable pore apertures for graded molecular sieving.

Membranes with high selectivity offer an attractive route to molecular separations, where technologies such as distillation and chromatography are energy intensive. However, it remains challenging to fine tune the structure and porosity in membranes, particularly to separate molecules of similar size. Here, we report a process for producing composite membranes that comprise crystalline porous organic cage films fabricated by interfacial synthesis on a polyacrylonitrile support. These membranes exhibit ultrafast solvent permeance and high rejection of organic dyes with molecular weights over 600 g mol-1. The crystalline cage film is dynamic, and its pore aperture can be switched in methanol to generate larger pores that provide increased methanol permeance and higher molecular weight cut-offs (1,400 g mol-1). By varying the water/methanol ratio, the film can be switched between two phases that have different selectivities, such that a single, 'smart' crystalline membrane can perform graded molecular sieving. We exemplify this by separating three organic dyes in a single-stage, single-membrane process.

Liquid Phase Peptide Synthesis via One-Pot Nanostar Sieving (PEPSTAR).

Herein, a one-pot liquid phase peptide synthesis featuring iterative addition of amino acids to a "nanostar" support, with organic solvent nanofiltration (OSN) for isolation of the growing peptide after each synthesis cycle is reported. A cycle consists of coupling, Fmoc removal, then sieving out of the reaction by-products via nanofiltration in a reactor-separator, or synthesizer apparatus where no phase or material transfers are required between cycles. The three-armed and monodisperse nanostar facilitates both efficient nanofiltration and real-time reaction monitoring of each process cycle. This enabled the synthesis of peptides more efficiently while retaining the full benefits of liquid phase synthesis. PEPSTAR was validated initially with the synthesis of enkephalin-like model penta- and decapeptides, then octreotate amide and finally octreotate. The crude purities compared favorably to vendor produced samples from solid phase synthesis.

N-Aryl-linked spirocyclic polymers for membrane separations of complex hydrocarbon mixtures.

The fractionation of crude-oil mixtures through distillation is a large-scale, energy-intensive process. Membrane materials can avoid phase changes in such mixtures and thereby reduce the energy intensity of these thermal separations. With this application in mind, we created spirocyclic polymers with N-aryl bonds that demonstrated noninterconnected microporosity in the absence of ladder linkages. The resulting glassy polymer membranes demonstrated nonthermal membrane fractionation of light crude oil through a combination of class- and size-based "sorting" of molecules. We observed an enrichment of molecules lighter than 170 daltons corresponding to a carbon number of 12 or a boiling point less than 200°C in the permeate. Such scalable, selective membranes offer potential for the hybridization of energy-efficient technology with conventional processes such as distillation.

Nanoscale Chemical Heterogeneity in Aromatic Polyamide Membranes for Reverse Osmosis Applications.

Reverse osmosis membranes are used within the oil and gas industry for seawater desalination on off-shore oilrigs. The membranes consist of three layers of material: a polyester backing layer, a polysulfone support and a polyamide (PA) thin film separating layer. It is generally thought that the PA layer controls ion selectivity within the membrane but little is understood about its structure or chemistry at the molecular scale. This active polyamide layer is synthesized by interfacial polymerization at an organic/aqueous interface between m-phenylenediamine and trimesoyl chloride, producing a highly cross-linked PA polymer. It has been speculated that the distribution of functional chemistry within this layer could play a role in solute filtration. The only technique potentially capable of probing the distribution of functional chemistry within the active PA layer with sufficient spatial and energy resolution is scanning transmission electron microscopy combined with electron energy-loss spectroscopy (STEM-EELS). Its use is a challenge because organic materials suffer beam-induced damage at relatively modest electron doses. Here we show that it is possible to use the N K-edge to map the active layer of a PA film using monochromated EELS spectrum imaging. The active PA layer is 12 nm thick, which supports previous neutron reflectivity data. Clear changes in the fine structure of the C K-edge across the PA films are measured and we use machine learning to assign fine structure at this edge. Using this method, we map highly heterogeneous intensity variations in functional chemistry attributed to N-C═C bonds within the PA. Similarities are found with previous molecular dynamics simulations of PA showing regions with a higher density of amide bonding as a result of the aggregation process at similar length scales. The chemical pathways that can be deduced may offer a clearer understanding of the transport mechanisms through the membrane.

Intrinsic modifiable risk factors in ballet dancers: Applying evidence based practice principles to enhance clinical applications.

INTRODUCTION: The risk of musculoskeletal injury is multifactorial (Bahr 2005). Injury risk is a composite of intrinsic and extrinsic risk factors that can be modifiable or non-modifiable. Ballet dancers have unique risk factors, due to the nature of their art and sport. The purpose of this literature review is to identify intrinsic modifiable risk factors for injury in ballet dancers. The secondary purpose is to investigate potential screening tools which can be used to identify these risk factors. METHODS: The authors performed a review of the literature in October 2017 within the databases of MEDLINE Complete, SPORTDiscus, and PubMed Central following a list of inclusion and exclusion criteria. RESULTS: A review of the available literature identified seven intrinsic modifiable factors specifically for ballet dancers and seven appropriate screening tools. DISCUSSION: The literature identified the most common intrinsic modifiable risk factors associated with ballet dancers to be: hypermobility, fatigue, overuse, neuromuscular dysfunction, degree of turnout, weakness of core and lower extremity musculature, and lower extremity range of motion (ROM) discrepancies. CONCLUSION: Sports medicine professionals who manage these performing artists can use this literature review to help develop injury prevention programs and enhance return to sport decision.

Author Correction: Sequence-defined multifunctional polyethers via liquid-phase synthesis with molecular sieving.

In the version of this Article originally published, the authors inadvertently cited ref. 10 in two places in the first paragraph. They would like to clarify that it should not have been cited in the sentence that starts "Polymer chemists have employed strategies such as single monomer insertion..." as it mistakenly implied that the IEG+ method described in ref. 10 could not produce unimolecular polymers; it can do so, as was demonstrated in ref. 10. The authors would also like to clarify that ref. 10 should not have been cited in the sentence that starts "Moreover, solid-phase synthesis is generally difficult to scale up...", as it implied that ref. 10 uses solid-phase synthesis; it does not, and is a purely liquid-phase process. The citation of ref. 10 has now been removed from these two sentences, but has been included elsewhere in the first two paragraphs of the Article as follows. In the first paragraph, at the end of the sentence "In iterative synthesis, specific monomers are added one at a time, or as multiples, to the end of a growing polymer chain, then reaction debris is separated from the chain extended polymer, and the cycle is repeated using the next monomer in the sequence10-12."; this sentence has been further amended to indicate multiple monomers can also be added. The reference has also been added to the end of the first sentence of the second paragraph, which starts "Consequently, liquid-phase iterative synthetic methods...", and in the third sentence of that paragraph, which now starts "For example, Johnson10, Whiting....".

Membrane Fractionation of Liquors from Lignin-First Biorefining.

For the utilization of each lignin fraction in the lignin liquors, the development of separation strategies to fractionate the lignin streams by molecular weight ranges constitutes a timely challenge to be tackled. Herein, membrane filtration was applied to the refining of lignin streams obtained from a lignin-first biorefining process based on H-transfer reactions catalyzed by Raney Ni, by using 2-PrOH as a part of the lignin extraction liquor and as an H-donor. A two-stage membrane cascade was considered to separate and concentrate the monophenol-rich fraction from the liquor. Building on the results, an economic evaluation of the potential of membrane filtration for the refining of lignin streams was undertaken. In this proof-of-concept report, a detailed analysis is presented of future developments in the performance required for the utilization of membrane filtration for lignin refining and, more aspiringly, solvent reclamation.

Sequence-defined multifunctional polyethers via liquid-phase synthesis with molecular sieving.

Synthetic chemists have devoted tremendous effort towards the production of precision synthetic polymers with defined sequences and specific functions. However, the creation of a general technology that enables precise control over monomer sequence, with efficient isolation of the target polymers, is highly challenging. Here, we report a robust strategy for the production of sequence-defined synthetic polymers through a combination of liquid-phase synthesis and selective molecular sieving. The polymer is assembled in solution with real-time monitoring to ensure couplings proceed to completion, on a three-armed star-shaped macromolecule to maximize efficiency during the molecular sieving process. This approach is applied to the construction of sequence-defined polyethers, with side-arms at precisely defined locations that can undergo site-selective modification after polymerization. Using this versatile strategy, we have introduced structural and functional diversity into sequence-defined polyethers, unlocking their potential for real-life applications in nanotechnology, healthcare and information storage.

Water Transport through Ultrathin Polyamide Nanofilms Used for Reverse Osmosis.

Thin-film composite membranes comprising a polyamide nanofilm separating layer on a support material are state of the art for desalination by reverse osmosis. Nanofilm thickness is thought to determine the rate of water transport through the membranes; although due to the fast and relatively uncontrolled interfacial polymerization reaction employed to form these nanofilms, they are typically crumpled and the separating layer is reported to be ≈50-200 nm thick. This crumpled structure has confounded exploration of the independent effects of thickness, permeation mechanism, and the support material. Herein, smooth sub-8 nm polyamide nanofilms are fabricated at a free aqueous-organic interface, exhibiting chemical homogeneity at both aqueous and organic facing surfaces. Transfer of these ultrathin nanofilms onto porous supports provides fast water transport through the resulting nanofilm composite membranes. Manipulating the intrinsic nanofilm thickness from ≈15 down to 8 nm reveals that water permeance increases proportionally with the thickness decrease, after which it increases nonlinearly to 2.7 L m-2 h-1 bar-1 as the thickness is further reduced to ≈6 nm.

Phosphorylated heat shock protein 27 as a potential biomarker to predict the role of chemotherapy-induced autophagy in osteosarcoma response to therapy.

Autophagy is a catabolic process involved in cellular homeostasis. Autophagy is increased above homeostatic levels by chemotherapy, and this can either promote or inhibit tumor growth. We previously demonstrated that aerosol gemcitabine (GCB) has a therapeutic effect against osteosarcoma (OS) lung metastases. However, some tumor cells failed to respond to the treatment and persisted as isolated lung metastasis. Here, we examined the mechanisms underlying the dual role of chemotherapy-induced autophagy in OS and sought to identify biomarkers to predict OS response to treatment. In this study, we demonstrate that treatment of various OS cells with GCB induced autophagy. We also showed that GCB reduces the phosphorylation of AKT, mTOR and p70S6K and that GCB-induced autophagy in OS can lead to either cell survival or cell death. Blocking autophagy enhanced the sensitivity of LM7 OS cells and decreased the sensitivity of CCH-OS-D and K7M3 OS cells to GCB. Using a kinase array, we also demonstrated that differences in the phosphorylated heat shock protein 27 (p-HSP27) expression in the various OS cell lines after treatment with GCB, correlates to whether chemotherapy-induced autophagy will lead to increase or decrease OS cells sensitivity to therapy. Increased p-HSP27 was associated with increased sensitivity to anticancer drug treatment when autophagy is inhibited. The results of this study reveal a dual role of autophagy in OS cells sensitivity to chemotherapy and suggest that p-HSP27 could represent a predictive biomarker of whether combination therapy with autophagy modulators and chemotherapeutic drugs will be beneficial for OS patients.

The Selectivity Challenge in Organic Solvent Nanofiltration: Membrane and Process Solutions.

Recent development of organic solvent nanofiltration (OSN) materials has been overwhelmingly directed toward tight membranes with ultrahigh permeance. However, emerging research into OSN applications is suggesting that improved separation selectivity is at least as important as further increases in membrane permeance. Membrane solutions are being proposed to improve selectivity, mostly by exploiting solute/solvent/membrane interactions and by fabricating tailored membranes. Because achieving a perfect separation with a single membrane stage is difficult, process engineering solutions, such as membrane cascades, are also being advocated. Here we review these approaches to the selectivity challenge, and to clarify our analysis, we propose a selectivity figure of merit that is based on the permselectivity between the two solutes undergoing separation as well as the ratio of their molecular weights.

Continuous Consecutive Reactions with Inter-Reaction Solvent Exchange by Membrane Separation.

Pharmaceutical production typically involves multiple reaction steps with separations between successive reactions. Two processes which complicate the transition from batch to continuous operation in multistep synthesis are solvent exchange (especially high-boiling- to low-boiling-point solvent), and catalyst separation. Demonstrated here is membrane separation as an enabling platform for undertaking these processes during continuous operation. Two consecutive reactions are performed in different solvents, with catalyst separation and inter-reaction solvent exchange achieved by continuous flow membrane units. A Heck coupling reaction is performed in N,N-dimethylformamide (DMF) in a continuous membrane reactor which retains the catalyst. The Heck reaction product undergoes solvent exchange in a counter-current membrane system where DMF is continuously replaced by ethanol. After exchange the product dissolved in ethanol passes through a column packed with an iron catalyst, and undergoes reduction (>99 % yield).