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Esa YH Chen,1,2 J Simon Bell,1–3 Jenni Ilomaki,2,3 Claire Keen,1 Megan Corlis,2,4 Michelle Hogan,4 Jan Van Emden,2,4 Sarah N Hilmer,2,5 Janet K Sluggett1,2 1Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; 2NHMRC Cognitive Decline Partnership Centre, Hornsby Ku-ring-gai Hospital, Hornsby, NSW, Australia; 3Department of Epidemiology and Preventive Medicine, School of Public Health and Preventative Medicine, Monash University, Melbourne, VIC, Australia; 4Helping Hand Aged Care, North Adelaide, SA, Australia; 5Kolling Institute, Faculty of Medicine and Health, The University of Sydney and Royal North Shore Hospital, St Leonards, NSW, AustraliaCorrespondence: Esa YH ChenCentre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, AustraliaTel +61 3 9903 9533Email Esa.Chen@monash.eduObjective: To explore variation in medication regimen complexity in residential aged care facilities (RACFs) according to resident age, length of stay, comorbidity, dementia severity, frailty, and dependence in activities of daily living (ADLs), and compare number of daily administration times and Medication Regimen Complexity Index (MRCI) as measures of regimen complexity.Methods: This study was a cross-sectional analysis of baseline data from the SImplification of Medications Prescribed to Long-tErm care Residents (SIMPLER) cluster-randomized controlled trial. The SIMPLER study recruited 242 residents with at least one medication charted for regular administration from 8 RACFs in South Australia. Comorbidity was assessed using the Charlson Comorbidity Index (CCI). Dementia severity was assessed using the Dementia Severity Rating Scale. Frailty was assessed using the FRAIL-NH scale. Dependence in ADLs was assessed using the Katz ADL scale.Results: The median age of participants was 87 years (interquartile range 81–92). Over one-third of participants (n=86, 36%) had 5 or more daily medication administration times. The number of daily administration times and MRCI scores were positively correlated with resident length of stay (rs=0.19; 0.27), FRAIL-NH score (rs=0.23; 0.34) and dependence in ADLs (rs=−0.21; −0.33) (all p

Esa YH Chen,1,2 Janet K Sluggett,1,2 Jenni Ilomäki,1,3 Sarah N Hilmer,2,4 Megan Corlis,2,5 Leonie J Picton,1 Laura Dean,1 Christopher P Alderman,6 Nicholas Farinola,7 Joy Gailer,8 Jane Grigson,5 Andrew R Kellie,9 Peter JC Putsey,5 Solomon Yu,10 J Simon Bell1–3 1Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; 2NHMRC Cognitive Decline Partnership Centre, Sydney Medical School – Northern, Hornsby Ku-ring-gai Hospital, Hornsby, NSW, Australia; 3Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; 4Kolling Institute, Sydney Medical School, The University of Sydney and Royal North Shore Hospital, St Leonards, NSW, Australia; 5Helping Hand Aged Care, North Adelaide, SA, Australia; 6School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia; 7Department of Clinical Pharmacology, Royal Adelaide Hospital, North Terrace, Adelaide, SA, Australia; 8Drug and Therapeutics Information Service, Repatriation General Hospital, Daw Park, SA, Australia; 9East Adelaide Healthcare, Newton, SA, Australia; 10Aged and Extended Care Services, The Queen Elizabeth Hospital, Woodville South, SA, Australia Background: Residents of aged care facilities use increasingly complex medication regimens. Reducing unnecessary medication regimen complexity (eg, by consolidating the number of administration times or using alternative formulations) may benefit residents and staff. Objective: To develop and validate an implicit tool to facilitate medication regimen simplification in aged care facilities. Method: A purposively selected multidisciplinary expert panel used modified nominal group technique to identify and prioritize factors important in determining whether a medication regimen can be simplified. The five prioritized factors were formulated as questions, pilot-tested using non-identifiable medication charts and refined by panel members. The final tool was validated by two clinical pharmacists who independently applied the tool to a random sample of 50 residents of aged care facilities to identify opportunities for medication regimen simplification. Inter-rater agreement was calculated using Cohen’s kappa.Results: The Medication Regimen Simplification Guide for Residential Aged CarE (MRS GRACE) was developed as an implicit tool comprising of five questions about 1) the resident; 2) regulatory and safety requirements; 3) drug interactions; 4) formulation; and 5) facility and follow-up considerations. Using MRS GRACE, two pharmacists independently simplified medication regimens for 29/50 and 30/50 residents (Cohen’s kappa=0.38, 95% CI 0.12–0.64), respectively. Simplification was possible for all residents with five or more administration times. Changing an administration time comprised 75% of the two pharmacists’ recommendations.Conclusions: Using MRS GRACE, two clinical pharmacists independently simplified over half of residents’ medication regimens with fair agreement. MRS GRACE is a promising new tool to guide medication regimen simplification in aged care. Keywords: medication therapy management, long-term care, geriatrics, drug administration, medication regimen complexity

Charcoal burning suicides in Hong Kong between 2002-2004 in the 15 to 59-year-old age group were investigated using the psychological autopsy method. The psychopathological profiles of charcoal burning suicides (N = 53) were compared against 'other suicides' (N = 97). The two groups did not differ significantly in the prevalence of DSM-IV axis I diagnoses with the exception of schizophrenic spectrum disorder which was less frequently associated with charcoal burning suicides. Score on 'neuroticism' in the NEO-five Factor Inventory (NEO-FFI) was significantly higher in victims of charcoal burning suicide. There was also a trend toward higher score on 'conscientiousness' in the NEO-FFI among charcoal burners than victims of other suicide. [ABSTRACT FROM AUTHOR]

We examined the rates of sexually transmitted diseases (STDs) in women with borderline personality disorder (BPD) (using PDE and SCID-II) and substance abuse or dependence (SCID-I) (BPD-SUD) (N=82) compared with those with BPD-only (N=102), exploring mediators of this relationship. Participants were interviewed about STD history (gonorrhea, genital herpes, syphilis, trichomonas, human papillomavirus, and HIV), condom use, number of sexual partners, poverty, and prostitution. BPD-SUD appeared to be particularly at high risk for STDs, reporting significantly more STDs than BPD (F[1,172]=11.74, p=0.001, d=.27), particularly for gonorrhea, trichomonas, and human papillomavirus. The relationship between BPD-SUD and STDs is mediated by poverty, prostitution in the last year, recent unprotected sex with two or more partners, and >20 lifetime partners (z=-2.16 which is p=0.03), with prostitution alone making a significant contribution to this relationship (z=-2.49, p=0.01). [ABSTRACT FROM AUTHOR]

Background. The global toll of suicide is estimated to be one million lives per year, which exceeded the number of deaths by homicide and war combined. A key step to suicide prevention is to prevent less serious suicidal behaviour to preclude more lethal outcomes. Although 61% of the world's suicides take place in Asia and the suicide rates among middle age groups have been increasing since the economic crisis in many Asian countries, population-based studies of suicidal behaviour among working-age adults in non-western communities are scarce.Method. Data from a population-based survey with 2015 participants were used to estimate the prevalence of suicidal ideation and behaviour among the working-age population in Hong Kong, and to study the associated socio-economic and psychological correlates. We focused particularly on potential modulating factors between life-event-related factors and suicidal ideation.Results. Six per cent of the Hong Kong population aged 20-59 years considered suicide in the past year, while 1.4% attempted suicide. Hopelessness, reasons for living, and reluctance to seek help from family and friends had direct association with past-year suicidal ideation. Reasons for living were found to moderate the effect of perceived stress on suicidal ideation.Conclusions. Suicidality is a multi-faceted problem that calls for a multi-sectored, multi-layered approach to prevention. Prevention programmes can work on modulating factors such as reasons for living to reduce suicidal risk in working-age adults. [ABSTRACT FROM AUTHOR]

This study investigated whether children would choose toys over candy when offered both on Halloween. Seven households gave trick-or-treaters a choice between comparably sized toys and candies. The subjects (N = 284) were between 3 and 14 years of age. Children were just as likely to choose toys as candy. There were no gender differences. The implication of this study is that children will not be disappointed by toy treats on Halloween. In practice, nutrition professionals should encourage adults to create holiday traditions that do not rely on unhealthful foods. [ABSTRACT FROM AUTHOR]

Microcystis bloom, a cyanobacterial mass occurrence often found in eutrophicated water bodies, is one of the most serious threats to freshwater ecosystems worldwide. In nature, Microcystis forms aggregates or colonies that contain heterotrophic bacteria. The Microcystis-bacteria colonies were persistent even when they were maintained in lab culture for a long period. The relationship between Microcystis and the associated bacteria was investigated by a metagenomic approach in this study. We developed a visualization-guided method of binning for genome assembly after total colony DNA sequencing. We found that the method was effective in grouping sequences and it did not require reference genome sequence. Individual genomes of the colony bacteria were obtained and they provided valuable insights into microbial community structures. Analysis of metabolic pathways based on these genomes revealed that while all heterotrophic bacteria were dependent upon Microcystis for carbon and energy, Vitamin B12 biosynthesis, which is required for growth by Microcystis, was accomplished in a cooperative fashion among the bacteria. Our analysis also suggests that individual bacteria in the colony community contributed a complete pathway for degradation of benzoate, which is inhibitory to the cyanobacterial growth, and its ecological implication for Microcystis bloom is discussed.

Independent Component analysis (ICA) is a widely used technique for separating signals that have been mixed together. In this manuscript, we propose a novel ICA algorithm using density estimation and maximum likelihood, where the densities of the signals are estimated via p-spline based histogram smoothing and the mixing matrix is simultaneously estimated using an optimization algorithm. The algorithm is exceedingly simple, easy to implement and blind to the underlying distributions of the source signals. To relax the identically distributed assumption in the density function, a modified algorithm is proposed to allow for different density functions on different regions. The performance of the proposed algorithm is evaluated in different simulation settings. For illustration, the algorithm is applied to a research investigation with a large collection of resting state fMRI datasets. The results show that the algorithm successfully recovers the established brain networks.

Microcystis aeruginosa is one of the most common and dominant bloom-forming cyanobacteria in freshwater lakes around the world. Microcystis cells can produce toxic secondary metabolites, such as microcystins, which are harmful to human health. Two M. aeruginosa strains were isolated from two highly eutrophic lakes in China and their genomes were sequenced. Comparative genomic analysis was performed with the 12 other available M. aeruginosa genomes and closely related unicellular cyanobacterium. Each genome of M. aeruginosa containing at least one clustered regularly interspaced short palindromic repeat (CRISPR) locus and total 71 loci were identified, suggesting it is ubiquitous in M. aeruginosa genomes. In addition to the previously reported subtype I-D cas gene sets, three CAS subtypes I-A, III-A and III-B were identified and characterized in this study. Seven types of CRISPR direct repeat have close association with CAS subtype, confirming that different and specific secondary structures of CRISPR repeats are important for the recognition, binding and process of corresponding cas gene sets. Homology search of the CRISPR spacer sequences provides a history of not only resistance to bacteriophages and plasmids known to be associated with M. aeruginosa, but also the ability to target much more exogenous genetic material in the natural environment. These adaptive and heritable defense mechanisms play a vital role in keeping genomic stability and self-maintenance by restriction of horizontal gene transfer. Maintaining genomic stability and modulating genomic plasticity are both important evolutionary strategies for M. aeruginosa in adaptation and survival in various habitats.

The translocon at the outer envelope membrane of chloroplasts (TOC) initiates the import of thousands of nuclear encoded preproteins required for chloroplast biogenesis and function. The multimeric TOC complex contains two GTP-regulated receptors, Toc34 and Toc159, which recognize the transit peptides of preproteins and initiate protein import through a β–barrel membrane channel, Toc75. Different isoforms of Toc34 and Toc159 assemble with Toc75 to form structurally and functionally diverse translocons, and the composition and levels of TOC translocons is required for the import of specific subsets of coordinately expressed proteins during plant growth and development. Consequently, the proper assembly of the TOC complexes is key to ensuring organelle homeostasis. This review will focus on our current knowledge of the targeting and assembly of TOC components to form functional translocons at the outer membrane. Our analyses reveal that the targeting of TOC components involves elements common to the targeting of other outer membrane proteins, but also include unique features that appear to have evolved to specifically facilitate assembly of the import apparatus.

For decades, implicit learning researchers have examined a variety of cognitive tasks in which people seem to automatically extract structure from the environment. Similarly, recent statistical learning studies have shown that people can learn word-object mappings from the repeated co-occurrence of words and objects in individually ambiguous situations. In light of this, the goal of the present paper is to investigate whether adult cross-situational learners require an explicit effort to learn word-object mappings, or if it may take place incidentally, only requiring attention to the stimuli. In two implicit learning experiments with incidental tasks directing participants' attention to different aspects of the stimuli, we found evidence of learning, suggesting that cross-situational learning mechanisms can operate incidentally, without explicit effort. However, performance was superior under explicit study instructions, indicating that strategic processes also play a role. Moreover, performance under instruction to learn word meanings did not differ from performance at counting co-occurrences, which may indicate these tasks engage similar strategies.

After fear conditioning, presenting the conditioned stimulus (CS) alone yields a context-specific extinction memory; fear is suppressed in the extinction context, but renews in any other context. The context-dependence of extinction is mediated by a brain circuit consisting of the hippocampus, prefrontal cortex and amygdala. In the present work, we sought to determine at what level of this circuit context-dependent representations of the CS emerge. To explore this question, we used cellular compartment analysis of temporal activity by fluorescent in situ hybridization (catFISH). This method exploits the intracellular expression profile of the immediate early gene, Arc, to visualize neuronal activation patterns to two different behavioral experiences. Rats were fear conditioned in one context and extinguished in another; twenty-four hours later, they were sequentially exposed to the CS in the extinction context and another context. Control rats were also tested in each context, but were never extinguished. We assessed Arc mRNA expression within the basal amygdala (BA), lateral amygdala (LA), ventral hippocampus (VH), prelimbic cortex (PL) and infralimbic cortex (IL). We observed that the sequential retention tests induced context-dependent patterns of Arc expression in the BA, LA, and IL of extinguished rats; this was not observed in non-extinguished controls. In general, non-extinguished animals had proportionately greater numbers of non-selective (double-labeled) neurons than extinguished animals. Collectively, these findings suggest that extinction learning results in pattern separation, particularly within the BA, in which unique neuronal ensembles represent fear memories after extinction.

In order to acquire their native languages, children must learn richly structured systems with regularities at multiple levels. While structure at different levels could be learned serially, e.g. speech segmentation coming before word-object mapping, redundancies across levels make parallel learning more efficient. For instance, a series of syllables is likely to be a word not only because of high transitional probabilities, but also because of a consistently co-occurring object. But additional statistics require additional processing, and thus might not be useful to cognitively constrained learners. We show that the structure of child-directed speech makes this problem solvable for human learners. First, a corpus of child-directed speech was recorded from parents and children engaged in a naturalistic free-play task. Analyses revealed two consistent regularities in the sentence structure of naming events. These regularities were subsequently encoded in an artificial language to which adult participants were exposed in the context of simultaneous statistical speech segmentation and word learning. Either regularity was sufficient to support successful learning, but no learning occurred in the absence of both regularities. Thus, the structure of child-directed speech plays an important role in scaffolding speech segmentation and word learning in parallel.

A growing set of data show that adults are quite good at accumulating statistical evidence across individually ambiguous learning contexts with multiple novel words and multiple novel objects (Fitneva & Christiansen, 2011; Kachergis, Yu, & Shiffrin, 2012; Yu & Smith, 2007; Yurovsky, Fricker, Yu, & Smith, under resubmission); experimental studies also indicate that infants and young children do this kind of learning as well (Smith & Yu, 2008; Vouloumanos & Werker, 2009). The present study provides evidence for the operation of selective attention in the course of cross-situational learning with two main goals. The first was to show that selective attention is critical for the underlying mechanisms that support successful cross-situational learning. The second one was to test whether an associative mechanism with selective attention can explain momentary gaze data in cross-situational learning. Toward these goals, we collected eye movement data from participants when they engaged in a cross-situational statistical learning task. Various gaze patterns were extracted, analyzed and compared between strong learners who acquired more word-referent pairs through training, and average and weak learners who learned fewer pairs. Fine-grained behavioural patterns from gaze data reveal how learners control their attention after hearing a word, how they selectively attend to individual objects which compete for attention within a learning trial, and how statistical evidence is accumulated trial by trial, and integrated across words, across objects, and across word-object mappings. Taken together, those findings from eye movements provide new evidence on the real-time statistical learning mechanisms operating in the human cognitive system.

Purpose: The aim of this study was to evaluate treatment results in our hypopharyngeal cancer patients.Patients and Methods: A total of three hundred and ninety five hypopharyngeal cancer patients received radical treatment at our hospital; 96% were male. The majority were habitual smokers (88%), alcohol drinkers (73%) and/or betel quid chewers (51%). All patients received a CT scan or MRI for tumor staging before treatment. The stage distribution was stage I: 2 (0.5%); stage II: 22 (5.6%); stage III: 57 (14.4%) and stage IV: 314 (79.5%). Radical surgery was used first in 81 patients (20.5%), and the remaining patients (79.5%) received organ preservation-intended treatment (OPIT). In the OPIT group, 46 patients received radiotherapy alone, 156 patients received chemotherapy followed by radiotherapy (CT/RT) and 112 patients received concomitant chemo-radiotherapy (CCRT).Results: The five-year overall survival rates for stages I/II, III and IV were 49.5%, 47.4% and 18.6%, respectively. There was no significant difference in overall and disease-specific survival rates between patients who received radical surgery first and those who received OPIT. In the OPIT group, CCRT tended to preserve the larynx better (p = 0.088), with three-year larynx preservation rates of 44.8% for CCRT and 27.2% for CT/RT. Thirty-seven patients developed a second malignancy, with an annual incidence of 4.6%.Conclusions: There was no survival difference between OPIT and radical surgery in hypopharyngeal cancer patients at our hospital. CCRT may offer better laryngeal preservation than RT alone or CT/RT. However, prospective studies are still needed to confirm this finding. Additionally, second primary cancers are another important issue for hypopharyngeal cancer management. [ABSTRACT FROM AUTHOR]

Despite decades of research and development, the optimal efficiency of slurry-packed HPLC columns is still hindered by inherent long-range flow heterogeneity from the wall to the central bulk region of these columns. Here, we show an example of how this issue can be addressed through the straightforward addition of a semidilute amount (500 ppm) of a large, flexible, synthetic polymer (18 MDa partially hydrolyzed polyacrylamide, HPAM) to the mobile phase (1% NaCl aqueous solution, hereafter referred to as "brine") during operation of a 4.6 mm × 300 mm column packed with 10μm BEH TM 125 Å particles. Addition of the polymer imparts elasticity to the mobile phase, causing the flow in the interparticle pore space to become unstable above a threshold flow rate. We verify the development of this elastic flow instability using pressure drop measurements of the friction factor versus Reynolds number. In prior work, we showed that this flow instability is characterized by large spatiotemporal fluctuations in the pore-scale flow velocities that may promote analyte dispersion across the column. Axial dispersion measurements of the quasi non-retained tracer thiourea confirm this possibility: they reveal that operating above the onset of the instability improves column efficiency by greater than 100%. These experiments thereby suggest that elastic flow instabilities can be harnessed to mitigate the negative impact of trans-column flow heterogeneities on the efficiency of slurry-packed HPLC columns. While this approach has its own inherent limitations and constraints, our results lay the groundwork for future targeted development of polymers that can impart elasticity when dissolved in commonly used liquid chromatography mobile phases, and can thereby generate elastic flow instabilities to help improve the resolution of HPLC columns., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Within the large poly(3-hydroxyalkanoate) (PHA) family, C3 propionates are much less studied than C4 butyrates, with the exception of α,α-disubstituted propionate PHAs, particularly poly(3-hydroxy-2,2-dimethylpropionate), P3H(Me) 2 P, due to its high melting temperature ( T m ∼ 230 °C) and crystallinity (∼76%). However, inefficient synthetic routes to its monomer 2,2-dimethylpropiolactone [(Me) 2 PL] and extreme brittleness of P3H(Me) 2 P largely hinder its broad applications. Here, we introduce simple, efficient step-growth polycondensation (SGP) of a hydroxyacid or methyl ester to afford P3H(Me) 2 P with low to medium molar mass, which is then utilized to produce lactones through base-catalyzed depolymerization. The ring-opening polymerization (ROP) of the 4-membered lactone leads to high-molar-mass P3H(Me) 2 P, which can be depolymerized by hydrolysis to the hydroxyacid in 99% yield or methanolysis to the hydroxyester in 91% yield, achieving closed-loop recycling via both SGP and ROP routes. Intriguingly, the chain end of the SGP-P3H(Me) 2 P determines the depolymerization selectivity toward 4- or 12-membered lactone formation, while both can be repolymerized back to P3H(Me) 2 P. Through the formation of copolymers P3H(Me/R) 2 P ( R = Et, n Pr), PHAs with high tensile strength and ductility, coupled with high barriers to water vapor and oxygen, have been created. Notably, the PHA structure-property study led to P3H( n Pr) 2 P with a record-high T m of 266 °C within the PHA family.

Asparagine synthetase (ASNS) catalyzes the biosynthesis of asparagine from aspartate and glutamine. Cells lacking ASNS, however, are auxotrophic for asparagine. Use of L-asparaginase to promote asparagine starvation in solid tumors with low ASNS levels, such as pancreatic ductal adenocarcinoma (PDAC), is a rationale treatment strategy. However, tumor cell resistance to L-asparaginase has limited its clinical utility. Our preclinical studies show that RAS/MAPK signaling circumvents L-asparaginase-induced tumor killing, but L-asparaginase and MEK inhibition potentiated tumor killing; suggesting that this combination may provide meaningful clinical benefit to patients with PDAC. This Phase I trial (NCT05034627) will evaluate the safety and tolerability of the MEK inhibitor, cobimetinib, in combination with pegylated L-asparaginase, L calaspargase pegol-mknl, in patients with locally-advanced or metastatic PDAC.

Neuroendocrine tumors (NETs) are a rare, heterogenous group of neoplasms arising from cells of the neuroendocrine system. Amongst solid tumor malignancies, NETs are notable for overall genetic stability and recent data supports the notion that epigenetic changes may drive NET pathogenesis. In this review, major epigenetic mechanisms of NET pathogenesis are reviewed, including changes in DNA methylation, histone modification, chromatin remodeling, and microRNA. Prognostic implications of the above are discussed, as well as the expanding diagnostic utility of epigenetic markers in NETs. Lastly, preclinical and clinical evaluations of epigenetically targeted therapies in NETs and are reviewed, with a focus on future directions in therapeutic advancement., Competing Interests: Declaration of competing interest I, Hannah McMurry, do not have and financial/personal competing interests related to the contents of the submitted manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Most patients treated with the standard dosing protocol (SDP) of hepatic arterial infusion (HAI) floxuridine require dose holds and reductions, thereby limiting their HAI therapy. We hypothesized that a modified dosing protocol (MDP) with a reduced floxuridine starting dose would decrease dose holds, dose reductions, and have similar potential to convert patients with unresectable colorectal liver metastases (uCRLM) to resection., Patients and Methods: We reviewed our institutional database of patients with uCRLM treated with HAI between 2016 and 2022. In 2019, we modified the floxuridine starting dose to 50% (0.06 mg/kg) of the SDP (0.12 mg/kg). We compared treatment related outcomes between the SDP and MDP cohorts., Results: Of n = 33 patients, 15 (45%) were treated on the SDP and 18 (55%) with our new institutional MDP. The MDP cohort completed more cycles before a dose reduction (mean 4.2 vs. 2), received more overall cycles (median 7.5 vs. 5), and averaged 39 more days of treatment (all P < 0.05). The SDP experienced more dose reductions (1.4 vs. 0.61) and dose holds (1.2 vs. 0.2; both P < 0.01). Of the patients in each group potentially convertible to hepatic resection, three patients (23%) in the SDP and six patients (35%) in the MDP group converted to resection (P = 0.691). Overall, four patients (27%) in the SDP developed treatment ending biliary toxicity compared with one patient (6%) in the MDP., Conclusions: A 50% starting dose of HAI floxuridine provides fewer treatment disruptions, more consecutive floxuridine cycles, and a similar potential to convert patients with initially uCRLM for disease clearance., (© 2024. Society of Surgical Oncology.)

T cell receptor (TCR)-T cell immunotherapy, in which T cells are engineered to express a TCR specific for a tumor epitope, is a form of adoptive cell therapy (ACT) that has demonstrated promise against various tumor types. Mutants of oncoprotein KRAS, particularly at glycine-12 (G12), are frequent drivers of tumorigenicity, but also attractive targets for TCR-T cell therapy. However, MHC class I-restricted TCRs specifically targeting G12-mutant KRAS epitopes in the context of tumors expressing HLA-A2, the most common human HLA-A allele, have remained elusive despite evidence that an epitope encompassing the mutation can bind HLA-A2 and induce T cell responses. We report that post-translational modifications of the protein on this epitope may allow tumor cells to evade immunologic pressure from TCR-T cells. A lysine side chain-methylated KRAS G12V peptide, rather than unmodified epitope, may be presented in HLA-A2 by tumor cells and impact recognition by TCRs. Using a novel computationally guided approach to design TCRs, we developed by mutagenesis TCRs that recognize this methylated peptide, enhancing tumor recognition and destruction. Additionally, we identified TCRs with similar functional activity in normal repertoires from rare primary T cells by stimulation with modified peptide, clonal expansion, and selection. Mechanistically, a gene knockout screen to identify mechanism(s) by which tumor cells methylate or demethylate this epitope unveiled SPT6 as a demethylating protein that could be targeted to improve effectiveness of these TCRs. These findings highlight the role of post-translational modifications in immune evasion and suggest that identifying and targeting such modifications should facilitate development of more effective TCR-T cell therapies.

We report the continuous, gas-phase synthesis of α-methylene-δ-valerolactone (MVL) from δ-valerolactone (DVL) and formaldehyde (FA) over alkaline earth oxide catalysts. MgO, CaO, and BaO supported on silica (∼5 wt%) were active for MVL production (613 K, 0.4 kPa DVL, 1.2 kPa FA, 101 kPa total pressure). CaO and BaO showed 90% and 83% selectivity to MVL at ∼60% DVL conversion, respectively. Decreasing contact times improved MVL selectivity for all three catalysts, achieving near quantitative selectivity at DVL conversions <40% with CaO. Further studies with CaO indicated that increasing the FA partial pressure for a given DVL partial pressure negligibly changed conversion while maintaining high selectivity; however, increasing the reaction temperature generally resulted in lower MVL selectivity. Deactivation and carbon loss were attributed to non-volatile compound formation from series and parallel reactions that consume MVL and DVL and poison the catalyst surface. These side reactions were more pronounced at high temperatures and higher contact times. While slow deactivation poses a challenge, the catalyst could be fully regenerated by calcining at 773 K for 4 h under flowing air. As the product mixture of MVL and DVL is difficult to separate, we developed a selective polymerization strategy to convert either one or both monomers into valuable polymeric materials, thereby achieving efficient separation and concurrent polymer production. Using a model mixture of 30 wt% of MVL in DVL, vinyl-addition polymerization converted MVL to the corresponding vinyl polymer (PMVL) VAP in 98% yield, while DVL was recovered in 96% yield by distillation. Alternatively, ring-opening polymerization of the same mixture resulted in a DVL/MVL copolyester and separatable vinyl homopolymer P(MVL) VAP ., Competing Interests: Some of the authors are inventors on patent application 63/675,565, submitted by the Massachusetts Institute of Technology, that covers the MVL synthesis method., (This journal is © The Royal Society of Chemistry.)

Developing a mechanistic understanding of catalyzed melt-phase depolymerization processes is of utmost importance to the rapidly expanding field of circular polymers with a closed chemical loop. Herein, we present a methodology to probe the mechanism of metal-catalyzed melt-phase depolymerization of polyesters utilizing an approach centered on studies of kinetics by thermogravimetric analysis and model reactions. Kinetic parameters associated with the prototypical Lewis-acid-catalyzed depolymerization of representative polyesters, including poly(δ-valerolactone) (PVL), poly(lactic acid), and poly(γ-butyrolactone), are elucidated. Focusing on PVL for further investigation of the depolymerization mechanism, effects of its molar mass, topology, and end-group chemistry are examined in detail. Overall, a catalyzed ring-closing depolymerization process to monomer from the polyester hydroxyl-chain ends is proposed as the key mechanistic step, although the process has a relatively large zip length (≈ 320) and follows nonimmortal depolymerization kinetics.

Background: Synchronous colorectal liver metastases may be managed with primary-first, simultaneous, or liver-first resection. Relative oncologic outcomes based upon treatment sequencing are understudied., Objective: This study aimed to assess oncologic survival outcomes in patients with synchronous colorectal liver metastases managed with each of the three treatment strategies, with respect to early or delayed removal of the primary tumor., Design: Retrospective analysis of prospectively maintained database, with 1:1 propensity-matching of relevant clinicopathologic variables comparing liver-first to primary-first/simultaneous approaches., Settings: Single-institution, tertiary cancer center., Patients: Patients undergoing curative-intent hepatectomy for synchronous colorectal liver metastases from 2003-2019., Main Outcome Measures: Overall and recurrence-free survival., Results: Of 151 patients, 23% (n = 35) had liver-first and 77% (n = 116; primary-first = 93 and simultaneous = 23) had primary-first/simultaneous approaches. Median follow-up was 45 months. Recurrence-free survival was worse for liver-first versus primary-first/simultaneous groups (median 12 versus 16 months, p = 0.02), driven by three-year extrahepatic recurrence-free survival of 19%, 58%, and 50% for liver-first, primary-first, and simultaneous groups, respectively. Three-year overall survival was not significantly different at 86%, 79%, and 86%, respectively. Oncologic outcomes did not significantly differ between primary-first and simultaneous groups (all p > 0.4). Matching yielded 34 clinicopathologically similar patients per group (liver-first = 34, primary-first = 28/simultaneous = 6). The liver-first approach was associated with shorter recurrence-free survival (median 12 versus 23 months, p = 0.004), driven by extrahepatic recurrence-free survival (3-year: 20% versus 55%, p = 0.04). Overall survival was not significantly different at 3-years (79% versus 80%, p = 0.95) or 5-years (59% versus 59%, p > 0.99)., Limitations: This study has a retrospective design and limited sample size., Conclusions: A liver-first approach is associated with worse recurrence free-survival compared to primary-first or simultaneous resection, driven by extrahepatic recurrence. Prospective study of whether oncologic risk is associated with leaving the primary in situ is needed. Multidisciplinary treatment sequencing and enhanced postoperative surveillance for patients receiving liver-first resection is recommended. See Video Abstract., (Copyright © The ASCRS 2024.)

Gases are essential for various applications relevant to human health, including in medicine, biomedical imaging, and pharmaceutical synthesis. However, gases are significantly more challenging to safely handle than liquids and solids. Herein, we review the use of porous materials, such as metal-organic frameworks (MOFs), zeolites, and silicas, to adsorb medicinally relevant gases and facilitate their handling as solids. Specific topics include the use of MOFs and zeolites to deliver H 2 S for therapeutic applications, 129 Xe for magnetic resonance imaging, O 2 for the treatment of cancer and hypoxia, and various gases for use in organic synthesis. This Perspective aims to bring together the organic, inorganic, medicinal, and materials chemistry communities to inspire the design of next-generation porous materials for the storage and delivery of medicinally relevant gases., (© 2024 Wiley-VCH GmbH.)

While a large number of chemically recyclable thermoplastics have been developed in recent years, technologically important thermoplastic elastomers (TPEs) that are not only bio-based and fully recyclable but also exhibit mechanical properties that can rival or even exceed those petroleum-based, non-recyclable polyolefin TPEs are critically lacking. The key challenge in developing chemically circular, bio-based, high-performance TPEs rests on the complexity of TPE's block copolymer (BCP) structure involving block segments of different suitable monomers required to induce self-assembled morphologies responsible for performance as well as the control and monomer compatibility in their synthesis and the selectivity in their depolymerization. Here we demonstrate the utilization of bio-sourced δ-valerolactone (δVL) and its simple α-alkyl-substituted derivatives to produce all δVL-based polyester tri-BCP TPEs, which exhibit not only complete (closed-loop) chemical recyclability but also excellent toughness that is 2.5-3.8 times higher than commercial polyolefin-based TPEs. The visualized cylindrical morphology formed via crystallization-driven self-assembly in the new all δVL tri-BCP is postulated to contribute to the excellent TPE property., (© 2024. The Author(s).)

Physical blending is an effective strategy for tailoring polymeric materials to specific application requirements. However, physically blended mixed plastics waste adds additional barriers in mechanical or chemical recycling. This difficulty arises from the intricate requirement for meticulous sorting and separation of the various polymers in the inherent incompatibility of mixed polymers during recycling. To overcome this impediment, this work furthers the emerging single-monomer - multiple-materials approach through the design of a bifunctional monomer that can not only orthogonally polymerize into two different types of polymers - specifically lactone-based polyester and CO 2 -based polycarbonate - but the resultant polymers and their mixture can also be depolymerized back to the single, original monomer when facilitated by catalysis. Specifically, the lactone/epoxide hybrid bifunctional monomer (BiL O ) undergoes ring-opening polymerization through the lactone manifold to produce polyester, PE(BiL O ), and is also applied to ring-opening copolymerization with CO 2 , via the epoxide manifold, to yield polycarbonate, PC(BiL O ). Remarkably, a one-pot recycling process of a BiL O -derived PE/PC blend back to the constituent monomer BiL O in >99 % selectivity was achieved with a superbase catalyst at 150 °C, thereby effectively obviating the requirement for sorting and separation typically required for recycling of mixed polymers., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: The incidence of early-onset colorectal cancer (EO-CRC) is rising in the United States, and is often diagnosed at advanced stages. Low serum ferritin is often incidentally discovered in young adults, however, the indication for endoscopy in EO-CRC is unclear., Aim: To compare serum ferritin between patients with EO-CRC and healthy controls (HCs), and examine the association of serum ferritin in EO-CRC with patient- and disease-specific characteristics., Methods: A retrospective study of patients < 50 years with newly-diagnosed EO-CRC was conducted from 1/2013-12/2023. Patients were included if serum ferritin was measured within 2 years prior to 1 year following CRC histologic diagnosis. To supplement the analysis, a cohort of HCs meeting similar inclusion and exclusion criteria were identified for comparison. A sensitivity analysis including only patients with serum ferritin obtained at or before diagnosis was separately performed to minimize risk of confounding., Results: Among 85 patients identified with EO-CRC (48 females), the median serum ferritin level was 26 ng/mL (range < 1-2759 ng/mL). Compared to HCs ( n = 80211), there were a higher proportion of individuals with EO-CRC with serum ferritin < 20 ng/mL (female 65%, male 40%) versus HCs (female 32.1%, male 7.2%) age 29-39 years ( P = 0.002 and P < 0.00001, respectively). Stage IV disease was associated with significantly higher serum ferritin compared to less advanced stages ( P < 0.001). Serum ferritin obtained before or at the time of diagnosis was lower than levels obtained after diagnosis. Similar findings were confirmed in the sensitivity analysis., Conclusion: Severe iron deficiency may indicate an increased risk of EO-CRC, particularly at earlier stages. Further studies defining the optimal serum ferritin threshold and routine incorporation of serum ferritin in screening algorithms is essential to develop more effective screening strategies for EO-CRC., Competing Interests: Conflict-of-interest statement: Shatzel JJ is supported by the National Heart, Lung, and Blood Institute/National Institutes of Health (No. R01HL151367); Shatzel JJ reports receiving consulting fees from Aronora Inc.; the remaining authors declare no conflicts of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

What Is This Summary About?: Researchers wanted to study whether the research drug zanidatamab could help people with a type of cancer called biliary tract cancer. In some people, biliary tract cancer cells make extra copies of a gene called HER2 (also called ERBB2). This is known as being HER2-amplified. Zanidatamab is an antibody designed to destroy cancer cells that have higher-than-normal HER2 protein or gene levels. Zanidatamab is currently under research and is not yet approved for any diseases. Participants in this phase 2b clinical study had tumors that were HER2-amplified and at the advanced or metastatic stage. Participants also had cancer which had become worse after previous chemotherapy or had side effects that were too bad to continue chemotherapy. They also had to meet other requirements to be enrolled. Researchers measured the amount of HER2 protein in the tumor samples of the participants who were enrolled. There were 80 participants with tumors that were both HER2 amplified and had higher-than-normal HER2 protein amounts (considered to be 'HER2-positive'). There were 7 participants with tumors that were HER2-amplified, but had little-to-no levels of the HER2 protein (considered to be 'HER2-low'). All participants in the study were treated with zanidatamab and no other cancer treatments once every 2 weeks., What Are the Key Takeaways?: In the HER2-positive group, 33 of 80 (41%) participants had their tumors shrink by 30% or more of their original size. In half of these participants, their tumors did not grow for 13 months or longer. No participant in the HER2-low group had their tumors shrink by 30% or more. In total, 63 of 87 participants (72%) had at least one side effect believed to be related to zanidatamab treatment. Most side effects were mild or moderate in severity. No participant died from complications related to zanidatamab. Diarrhea was one of the more common side effects and was experienced by 32 of 87 participants (37%). Side effects related to receiving zanidatamab through the vein, such as chills, fever, or high blood pressure, were experienced by 29 of 87 participants (33%)., What Are the Conclusions Reported by the Researchers?: The results of this study support the potential for zanidatamab as a new therapy for people with HER2-positive biliary tract cancer after they had already received chemotherapy. More research is occurring to support these results. Clinical Trial Registration: NCT04466891 (HERIZON-BTC-01 study).

Immunotherapy is considered first line in patients with dMMR metastatic colorectal cancer (CRC). Recent studies have also shown promising results with neoadjuvant immunotherapy in locally advanced CRC. We report a case in which neoadjuvant immunotherapy with pembrolizumab resulted in complete pathologic response at time of resection as well as saved the patient the morbidity associated with a hepatectomy. We also completed a scoping review of the literature which suggests promising tumor responses with treatment in dMMR CRC. Further randomized control trials to determine the magnitude of response and optimal regimen are needed., Competing Interests: All authors have no conflicts of interest to disclose., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Radiotherapy (RT) plays a critical role in the management of rhabdomyosarcoma (RMS), the prevalent soft tissue sarcoma in childhood. The high risk PAX3-FOXO1 fusion-positive subtype (FP-RMS) is often resistant to RT. We have recently demonstrated that inhibition of class-I histone deacetylases (HDACs) radiosensitizes FP-RMS both in vitro and in vivo. However, HDAC inhibitors exhibited limited success on solid tumors in human clinical trials, at least in part due to the presence of off-target effects. Hence, identifying specific HDAC isoforms that can be targeted to radiosensitize FP-RMS is imperative. We, here, found that only HDAC3 silencing, among all class-I HDACs screened by siRNA, radiosensitizes FP-RMS cells by inhibiting colony formation. Thus, we dissected the effects of HDAC3 depletion using CRISPR/Cas9-dependent HDAC3 knock-out (KO) in FP-RMS cells, which resulted in Endoplasmatic Reticulum Stress activation, ERK inactivation, PARP1- and caspase-dependent apoptosis and reduced stemness when combined with irradiation compared to single treatments. HDAC3 loss-of-function increased DNA damage in irradiated cells augmenting H2AX phosphorylation and DNA double-strand breaks (DSBs) and counteracting irradiation-dependent activation of ATM and DNA-Pkcs as well as Rad51 protein induction. Moreover, HDAC3 depletion hampers FP-RMS tumor growth in vivo and maximally inhibits the growth of irradiated tumors compared to single approaches. We, then, developed a new HDAC3 inhibitor, MC4448, which showed specific cell anti-tumor effects and mirrors the radiosensitizing effects of HDAC3 depletion in vitro synergizing with ERKs inhibition. Overall, our findings dissect the pro-survival role of HDAC3 in FP-RMS and suggest HDAC3 genetic or pharmacologic inhibition as a new promising strategy to overcome radioresistance in this tumor., (© 2024. The Author(s).)

The selective synthesis of ultrahigh-molar-mass (UHMM, >2 million Da) cyclic polymers is challenging as an exceptional degree of spatiotemporal control is required to overcome the possible undesired reactions that can compete with the desired intramolecular cyclization. Here we present a counterintuitive synthetic methodology for cyclic polymers, represented here by polythioesters, which proceeds via superbase-mediated ring-opening polymerization of gem-dimethylated thiopropiolactone, followed by macromolecular cyclization triggered by protic quenching. This proton-triggered linear-to-cyclic topological transformation enables selective, linear polymer-like access to desired cyclic polythioesters, including those with UHMM surpassing 2 MDa. In addition, this method eliminates the need for stringent conditions such as high dilution to prevent or suppress linear polymer contaminants and presents the opposite scenario in which protic-free conditions are required to prevent cyclic polymer formation, which is capitalized to produce cyclic polymers on demand. Furthermore, such UHMM cyclic polythioester exhibits not only much enhanced thermostability and mechanical toughness, but it can also be quantitatively recycled back to monomer under mild conditions due to its gem-disubstitution., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

We present the vibrational properties and phonon dispersion for quasi-2D hybrid organic-inorganic perovskites (BA) 2 CsPb 2 I 7 , (HA) 2 CsPb 2 I 7 , (BA) 2 (MA)Pb 2 I 7 , and (HA) 2 (MA)Pb 2 I 7 calculated from first principles. Given the highly complex nature of these compounds, we first perform careful benchmarking and convergence testing to identify suitable parameters to describe their structural features and vibrational properties. We find that the inclusion of van der Waals corrections on top of generalized gradient approximation (GGA) exchange-correlation functionals provides the best agreement for the equilibrium structure relative to experimental data. We also investigate the impact of the molecular orientation on the equilibrium structure of these layered perovskite systems. Our results suggest ground state ferroelectric alignment of molecular dipoles in the out-of-plane direction is unlikely and support the assignment of the centrosymmetric space group for the low-temperature phase of (HA) 2 (MA)Pb 2 I 7 . Finally, we compute vibrational properties under the harmonic approximation. We find that stringent energy cut-offs are required to obtain well-converged phonon properties, and once converged, the harmonic approximation can capture key physics for such a large, hybrid inorganic-organic system with vastly different atom types, masses, and interatomic interactions. We discuss the obtained phonon modes and dispersion behavior in the context of known properties for bulk 3D perovskites and ligand molecular crystals. While many vibrational properties are inherited from the parent systems, we also observe unique coupled vibrations that cannot be associated with vibrations of the pure constituent perovskite and ligand subphases. Energy dispersion of the low energy phonon branches primarily occurs in the in-plane direction and within the perovskite subphase and arises from bending and breathing modes of the equatorial Pb-I network within the perovskite octahedral plane. The analysis herein provides the foundation for future investigations on this class of materials, such as exciton-phonon coupling, phase transitions, and general temperature-dependent properties., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)