Healthcare delivery to patients from culturally and linguistically diverse backgrounds in emergency care: a scoping review protocol.

BACKGROUND: Worldwide, the culturally and linguistically diverse (CALD) population is increasing, and is predicted to reach 405 million by 2050. The delivery of emergency care for the CALD population can be complex due to cultural, social, and language factors. The extent to which cultural, social, and contextual factors influence care delivery to patients from CALD backgrounds throughout their emergency care journey is unclear. Using a systematic approach, this review aims to map the existing evidence regarding emergency healthcare delivery for patients from CALD backgrounds and uses a social ecological framework to provide a broader perspective on cultural, social, and contextual influence on emergency care delivery. METHODS: The Joanna Briggs Institute (JBI) scoping review methodology will be used to guide this review. The population is patients from CALD backgrounds who received care and emergency care clinicians who provided direct care. The concept is healthcare delivery to patients from CALD backgrounds. The context is emergency care. This review will include quantitative, qualitative, and mixed-methods studies published in English from January 1, 2012, onwards. Searches will be conducted in the databases of CINAHL (EBSCO), MEDLINE (Ovid), Embase (Elsevier), SocINDEX (EBSCO), Scopus (Elsevier), and a web search of Google Scholar. A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram will be used to present the search decision process. All included articles will be appraised using the Mixed Methods Appraisal Tool (MMAT). Data will be presented in tabular form and accompanied by a narrative synthesis of the literature. DISCUSSION: Despite the increased use of emergency care service by patients from CALD backgrounds, there has been no comprehensive review of healthcare delivery to patients from CALD backgrounds in the emergency care context (ED and prehospital settings) that includes consideration of cultural, social, and contextual influences. The results of this scoping review may be used to inform future research and strategies that aim to enhance care delivery and experiences for people from CALD backgrounds who require emergency care. SYSTEMATIC REVIEW REGISTRATION: This scoping review has been registered in the Open Science Framework https://doi.org/10.17605/OSF.IO/HTMKQ.

The Physical Health Nurse Consultant: Perceptions and Experiences of Those Who Care for People with Mental Illness.

Mental health carers are crucial in improving the physical health outcomes of people diagnosed with a mental illness (hereafter referred to as consumers). The long-term and multifaceted mental and physical health support carers provide to consumers can contribute to caregiver burden. Consequently, carers advocate for coordinated and integrated physical healthcare to improve the physical health outcomes of consumers and alleviate caregiver burden. The aim of this qualitative exploratory study is to explore carers' perceptions and experiences with the Physical Health Nurse Consultant role. Semi-structured interviews with nine carers nominated by consumers were conducted. Interviews were transcribed and reflexively thematically analysed. Three main themes were identified: (i) Therapeutic relationship s were a catalyst for health behaviour change; (ii) Overt and covert positive changes were observed by carer and (iii) Cares' involvement in integrated mental health and physical health care. Nine carers who were nominated by consumers to be involved in their physical healthcare planning, preferred to adopt a supporting role as this prevented or reduced caregiver burden. The findings support the adoption and continuation of the Physical Health Nurse Consultant role to facilitate positive physical health outcomes for consumers and a reduction in caregiving burden. The benefits of the Physical Health Nurse Consultant provide a compelling argument to embed the role in routine practice. Mental healthcare services should advocate for continued funding and career development for such positions to provide long term benefits for consumers and carers. Future research is required to explore carer and consumer involvement in co-producing future and localised iterations of the Physical Health Nurse Consultant role. This research should also measure the outputs and outcomes of co-production to clarify how the process worked in practice.

Anti-biofilm activities and antibiotic synergy of naturally occurring compounds against drug-resistant rapidly growing mycobacteria.

Some naturally occurring compounds, known for their antimicrobial activities, have been employed as food additives. However, their efficacy in treating infections caused by antibiotic-resistant bacteria is yet to be fully explored. Rapidly growing mycobacteria (RGM), a category within nontuberculous mycobacteria (NTM), are prevalent in various environments and can lead to infections in humans. The rise of antimicrobial resistance within RGM is a documented concern. In this study, we reported that four specific natural compounds effectively inhibited the growth and biofilm formation of three key RGM pathogens M. abscessus, M. fortuitum, and M. chelonae. We screened 12 natural compounds for their effectiveness against antibiotic-resistant clinical strains of RGM. Four compounds showed significant inhibitory effects from the most effective to least: trans-cinnamaldehyde, carvacrol, gentisaldehyde, and phloroglucinaldehyde. In the analysis of time-killing kinetics, gentisaldehyde and phloroglucinaldehyde displayed bactericidal activity while trans-cinnamaldehyde and carvacrol exhibited bacteriostatic effects. At 1× minimal inhibition concentrations, these compounds significantly reduced biofilm formation in all three RGM species to levels between 2.9% and 20.5% relative to controls. Checkerboard assays indicated synergistic interactions between these four compounds and antibiotics such as amikacin, clarithromycin, and linezolid. Of these 12 compound-antibiotic combinations, the pairs of carvacrol-linezolid, carvacrol-amikacin, and gentisaldehyde-clarithromycin demonstrated the most synergy against multiple RGM strains. Moreover, two other compounds citral and geraniol showed synergism with all three test antibiotics. Time-killing assays further confirmed most of synergistic combinations identified in the checkerboard tests. Our research suggests the potential of these essential oils and phenolic aldehydes, both individually and in combination with antibiotics, in treating RGM infections. In addition, this work illuminates applications of these natural compounds in environmental remediation to mitigate bacterial persistence for the control of infectious diseases. IMPORTANCE: The emergence of antimicrobial resistance within rapidly growing mycobacteria (RGM) poses a significant threat to public health. This study investigates the potential of naturally occurring compounds to combat infections caused by antibiotic-resistant RGM including M. abscessus, M. fortuitum, and M. chelonae. We identified four specific natural compounds showing impressive inhibitory effects against antibiotic-resistant clinical strains. These compounds not only inhibited the growth and biofilm formation but also exhibited synergistic interactions with antibiotics against key RGM pathogens. Our findings highlight the alternative treatment strategies for RGM infections and potential environmental applications of these natural compounds in mitigating microbial persistence and controlling infectious diseases.

Unraveling chemical changes associated with the sensory quality of Chinese steamed bread as altered by wheat flour type.

Chinese steamed bread (CSB) is an important staple of the Chinese people, and its flavor profile is mostly affected by wheat varieties among others. This study selected wheat flour made from three different wheat varieties and investigated their contribution to the CSB flavor profile in terms of metabolism. Thirteen aroma-active compounds identified by GC-O were determined as the main contributors to the different aroma profiles of three CSBs. 350 sensory trait-related metabolites were obtained from five key modules via weighted gene co-expression network analysis. It was found that the sensory characteristics of CSBs made of different wheat flour were significantly different. The higher abundance of lipids in Yongliang No.4 (YL04) wheat flour was converted to large number of fatty acids in fermented dough, which led to the bitterness of CSB. Besides, the abundance in organic acids and fatty acids contributed to the sour, milky, wetness and roughness attributes of YL04-CSB. More fatty amides and flavonoids in Jiangsu Red Durum wheat flour contributed to the fermented and winey attributes of CSB. Carbohydrates with higher abundance in Canadian wheat flour was involved in sugar-amine reaction and glucose conversion, which enhanced the sweetness of CSB. In addition, fatty acids, organic acids, amino acids, and glucose were crucial metabolites which can further formed into various characteristic compounds such as hexanal, hexanol, 2,3-butanediol, acetoin, and 2,3-butanedione and thus contributed to the winey, fresh sweet, and green aroma properties. This study is conductive to better understand the evolution of the compounds that affect the quality and aroma of CSBs.

Mapping the CP-Transgene Insert in the Papaya Genome and Developing a Hermaphrodite Transgenic Hybrid with Broad-Spectrum Resistance to Papaya Ringspot Virus.

Papaya ringspot virus (PRSV) limits papaya production worldwide. Previously, we generated transgenic lines of hybrid Tainung No.2 (TN-2) carrying the coat protein (CP) gene of PRSV with broad resistance to PRSV strains. Unfortunately, all of them were female, unacceptable for growers and consumers in practical applications. With our reported flanking sequences and the newly released papaya genomic information, the CP-transgene insert was identified at a non-coding region in chromosome 3 of the papaya genome, and the flanking sequences were verified and extended. The female transgenic line 16-0-1 was first used for backcrossing with the parental Sunrise cultivar six times and then followed by selfing three times. With multi-level molecular markers developed from the PRSV CP transgene and the genomic flanking sequences, the presence and zygosity of the CP transgene were characterized at the seedling stage. Meanwhile, hermaphrodite genotype was identified by a sex-linked marker. With homozygotic transgene and horticultural properties of Sunrise, a selected hermaphrodite individual was propagated by tissue culture (TC) and used as maternal progenitor to cross with non-transgenic parental cultivar Thailand to generate a new hybrid cultivar TN-2 with a hemizygotic CP-transgene. Three selected hermaphrodite individuals of transgenic TN were micropropagated by TC, and they showed broad-spectrum resistance to different PRSV strains from Taiwan, Hawaii, Thailand, and Mexico under greenhouse conditions. The selected clone TN-2 #1, with excellent horticultural traits, also showed complete resistance to PRSV under field conditions. These selected TC clones of hermaphrodite transgenic TN-2 provide a novel cultivation system in Taiwan and elsewhere.

Molecular surveillance of Helicobacter species with high prevalence from two streams with various wastewater pollution in Taiwan.

Helicobacter species are potential zoonotic pathogens classified as either enterohepatic or gastric. Helicobacter infection can be transmitted through wastewater from households and livestock and through water from irrigation and streams. In this study, the distribution and source of Helicobacter species in the Donggang and Yenshui rivers, two natural water bodies with different characteristics, were analyzed. A total of 44 water samples were collected over the four seasons. The samples were subjected to Helicobacter 16 s rRNA gene PCR, followed by sequencing and comparison for identification and analysis. The detection rate of Helicobacter species in both rivers was 79.55%, with H. kayseriensis (10/35, 28.57%) being the most common species. Analysis of the environment around the sampling sites showed a high detection rate in the livestock-rich area, and the results of BLAST for species identification and comparison indicated feces as the contamination source. The area around the Donggang River was developed for animal husbandry, led to a high detection rate of Helicobacter species. Many Helicobacter species were identified to have a risk of zoonotic transmission, especially if the stream is used as a source of drinking, agricultural, or even aquacultural water. The high presence of Helicobacter species in natural water bodies suggests that wastewater treatment is an effective strategy to control pathogen spread. Therefore, investigation and monitoring of pathogens in wastewater are highly important. However, methods for the isolation and culture of Helicobacter species in natural waters have yet to be developed. Hence, future research should focus on developing such methods.

The epidemiology of dying within 48 hours of presentation to emergency departments: a retrospective cohort study of older people across Australia and New Zealand.

BACKGROUND: Emergency department (ED) clinicians are more frequently providing care, including end-of-life care, to older people. OBJECTIVES: To estimate the need for ED end-of-life care for people aged ≥65 years, describe characteristics of those dying within 48 hours of ED presentation and compare those dying in ED with those dying elsewhere. METHODS: We conducted a retrospective cohort study analysing data from 177 hospitals in Australia and New Zealand. Data on older people presenting to ED from January to December 2018, and those who died within 48 hours of ED presentation, were analysed using simple descriptive statistics and univariate logistic regression. RESULTS: From participating hospitals in Australia or New Zealand, 10,921 deaths in older people occurred. The 48-hour mortality rate was 6.43 per 1,000 ED presentations (95% confidence interval: 6.31-6.56). Just over a quarter (n = 3,067, 28.1%) died in ED. About one-quarter of the cohort (n = 2,887, 26.4%) was triaged into less urgent triage categories. Factors with an increased risk of dying in ED included age 65-74 years, ambulance arrival, most urgent triage categories, principal diagnosis of circulatory system disorder, and not identifying as an Aboriginal or Torres Strait Islander person. Of the 7,677 older people admitted, half (n = 3,836, 50.0%) had an encounter for palliative care prior to, or during, this presentation. CONCLUSIONS: Our findings provide insight into the challenges of recognising the dying older patient and differentiating those appropriate for end-of-life care. We support recommendations for national advanced care planning registers and suggest a review of triage systems with an older person-focused lens.

The impact of COVID-19 on emergency department presentations for mental health disorders in Queensland, Australia: A time series analysis.

BACKGROUND: The COVID-19 pandemic has been associated with detrimental effects on mental health and psychological well-being. Although multiple studies have shown decreases in mental health-related Emergency Department (ED) presentations early in the COVID-19 pandemic, the medium-term effects on mental health-related ED presentations have remained less clear. This study aimed to evaluate the effect of the pandemic on mental health ED presentations by comparing observed presentation numbers to predictions from pre-pandemic data. METHODS: This retrospective cohort study tallied weekly ED presentations associated with mental health disorders from a state-wide minimum dataset. Three time periods were identified: Pre-Pandemic (January 1, 2018-March 8, 2020), Statewide Lockdown (March 9, 2020-June 28, 2020), and Restrictions Easing (June 29, 2020-June 27, 2021). Time series analysis was used to generate weekly presentation forecasts using pre-pandemic data. Observed presentation numbers were compared to these forecasts. RESULTS: Weekly presentation numbers were lower than predicted in 11 out of 16 weeks in the Statewide Lockdown period and 52 out of 52 weeks in the Restrictions Easing period. The largest decrease was seen for anxiety disorders (Statewide Lockdown: 76.8% of forecast; Restrictions Easing: 36.4% of forecast), while an increase was seen in presentations for eating disorders (Statewide Lockdown: 139.5% of forecast; Restrictions Easing: 194.4% of forecast). CONCLUSIONS: Overall weekly mental health-related presentations across Queensland public EDs were lower than expected for the first 16 months of the COVID-19 pandemic. These findings underline the limitations of emergency department provision of mental health care and the importance of alternate care modalities in the pandemic context.

Contamination Status and Acute Dietary Exposure Assessment of Paralytic Shellfish Toxins in Shellfish in the Dalian Area of the Yellow-Bohai Sea, China.

The Yellow-Bohai Sea is an important semi-enclosed continental shelf marginal seas with an intensive aquaculture industry in China. The current study analyzed the contamination status and the time variations of paralytic shellfish toxins (PSTs) in shellfish between 2019 and 2020 from the Yellow-Bohai Sea in the Dalian area and estimated the acute health risks to consumers in China. A total of 199 shellfish samples (including 34 Pacific oysters, 25 Mediterranean blue mussels, 34 Manila clams, 36 bay scallops, 34 veined rapa whelks and 36 bloody clams) were analyzed from four representative aquaculture zones around the Yellow-Bohai Sea in Dalian. Among the samples, scallops and blood clams were the shellfish species with the highest detection rate of PSTs (94.4%), and the highest level of PSTs was detected in scallops with 3953.5 µg STX.2HCl eq./kg (µg STX.2HCL equivalents per kg shellfish tissue), followed by blood clams with 993.4 µg STX.2HCl eq./kg. The contents of PSTs in shellfish showed a time variation trend, and autumn was the season of concern for PST contamination in Dalian. For general Chinese consumers, the probability of acute health risks to shellfish consumers from dietary exposure to PSTs was around 13%. For typical consumers in coastal areas of China, especially those with higher shellfish intake, there was an acute health risk associated with exposure to PSTs through shellfish consumption during the occurrence of harmful algal blooms. It is suggested that the government continue to strengthen the monitoring of the source of PSTs and the monitoring of harmful algal blooms and give reasonable advice on shellfish consumption for consumers in coastal areas, such as not eating scallop viscera.

The impact of index futures crash risk on bitcoin futures returns and volatility.

This study examines the relationship between E-mini S&P 500 futures' crash risk and Bitcoin futures' returns and volatility using data from 2017 to 2021. While E-mini S&P 500's crash risk doesn't significantly influence Bitcoin returns, it correlates with its volatility, especially during events like the COVID-19 pandemic and U.S. elections. Furthermore, as global and emerging market indices rise, Bitcoin futures volatility decreases, suggesting its role as a hedging tool. These findings are pivotal for investors aiming to construct informed trading strategies, leverage Bitcoin futures as a hedging asset during economic instability, and keep tabs on traditional market indicators like E-mini S&P 500 crash risk for anticipating fluctuations in Bitcoin futures.

End-of-life care: A retrospective cohort study of older people who died within 48 hours of presentation to the emergency department.

OBJECTIVES: To describe the characteristics of, and care provided to, older people who died within 48 h of ED presentation. METHODS: A descriptive retrospective cohort study of people 65 years and older presenting to two EDs in Queensland, Australia, between April 2018 and March 2019. Data from electronic medical records were collected and analysed. RESULTS: Two hundred and ninety-five older people who died within 48 h of ED presentation were included. Nearly all arrived by ambulance (92%, n = 272) and 36% (n = 106) were from aged care facilities. Three-quarters (75%, n = 222) were triaged into the most urgent triage categories (i.e. Australasian Triage Scale; ATS 1/2). Fewer than half were previously independent with mobility (38%, n = 111) and activities of daily living (43%, n = 128). Sixty-one per cent (n = 181) had a pre-existing healthcare directive. Twenty-two per cent (n = 66) died in ED, most commonly due to pneumonia, intracerebral haemorrhage, cardiac arrest and/or sepsis. Over half had one or more ED visits (52%, n = 154) and/or hospital admissions (52%, n = 152) 6 months prior. CONCLUSIONS: Identification of patients at end-of-life (EoL) is not always straightforward; consider recent reduction in independence and recent ED visits/hospital admissions. System-based strategies that span pre-hospital, ED and in-patient care are recommended to facilitate EoL pathway implementation and care continuity.

Adults' perspectives of experiences and preferences for end-of-life care.

BACKGROUND: Decisions about end-of-life care often raise clinical and ethical challenges, especially when the person's capacity to contribute in the decision making at the end of life is limited. AIM: This study aimed to explore Taiwanese adults' preferences associated with communication, healthcare planning, life-sustaining treatments and palliative care and experiences of end-of-life care. METHODS: Semi-structured interviews were conducted with 16 adults aged 20 years and above. The sampling approach was a convenience strategy in a community centre located in a metropolitan area in the Southern region of Taiwan. A qualitative content analysis approach was used to elicit key themes from the data. RESULTS: Significant findings related to the two main themes of adults' experiences, including the observed distress of those who were dying and the distress experienced by the family. Other key findings pertain to personal preferences for end-of-life care, such as preferred end-of-life communication, preparing for the end-of-life and maintenance of quality of life. CONCLUSIONS: This exploratory study offers insight into 16 Taiwanese community-dwelling adults' views of preferences regarding end-of-life communication, preparation for the end of life and maintenance of quality of life, as well as their experiences of end-of-life care. A further exploration is suggested to elicit how personal end-of-life experiences shape individuals' health practices in advance care planning for end-of-life care.

Single cell multi-omics reveal intra-cell-line heterogeneity across human cancer cell lines.

Human cancer cell lines have long served as tools for cancer research and drug discovery, but the presence and the source of intra-cell-line heterogeneity remain elusive. Here, we perform single-cell RNA-sequencing and ATAC-sequencing on 42 and 39 human cell lines, respectively, to illustrate both transcriptomic and epigenetic heterogeneity within individual cell lines. Our data reveal that transcriptomic heterogeneity is frequently observed in cancer cell lines of different tissue origins, often driven by multiple common transcriptional programs. Copy number variation, as well as epigenetic variation and extrachromosomal DNA distribution all contribute to the detected intra-cell-line heterogeneity. Using hypoxia treatment as an example, we demonstrate that transcriptomic heterogeneity could be reshaped by environmental stress. Overall, our study performs single-cell multi-omics of commonly used human cancer cell lines and offers mechanistic insights into the intra-cell-line heterogeneity and its dynamics, which would serve as an important resource for future cancer cell line-based studies.

Inactivation Kinetics of Foodborne Pathogens in Carrot Juice by High-Pressure Processing.

In this study, Salmonella Typhimurium, Escherichia coli, and Listeria monocytogenes were separately inoculated in sterilized carrot juice and subjected to various types of high-pressure processing (HPP) at 200-600 MPa for 0.1-15 min to observe the effects of HPP on the inactivation kinetics of foodborne pathogens in carrot juice. The first-order model fits the destruction kinetics of high pressure on foodborne pathogens during the pressure hold period. An increase in pressure from 200 to 600 MPa decreased the decimal reduction time (D values) of S. Typhimurium, E. coli, and L. monocytogenes. Under pressure ≥ 400 MPa, the D values of E. coli were significantly higher than those of S. Typhimurium and L. monocytogenes, indicating that E. coli had greater resistance to high pressures than the others. The Zp values (the pressure range that causes the D values to change by 90%) of E. coli, S. Typhimurium, and L. monocytogenes were 195, 175, and 170 MPa, respectively. These results indicated that L. monocytogenes and E. coli were the most and least sensitive, respectively, to pressure changes. Additionally, the three bacteria were separately inoculated into thermal-sterilized carrot juice and subjected to 200-600 MPa HPP for 3 min. The treated carrot juices were stored at 4 °C for 27 d. Following S. Typhimurium and E. coli inoculation, the bacterial counts of the control and 200 MPa treatments remained the same during the storage duration. However, they decreased for the 300 and 400 MPa treatment groups with increasing storage duration. During the storage period, no bacterial growth was observed in the 500 and 600 MPa treatments. However, the bacterial number for the control and pressure treatment groups increased with prolonged storage duration following inoculation with L. monocytogenes. Therefore, following HPP, residual L. monocytogenes continued growing stably at low temperatures. Overall, HPP could inhibit and delay the growth of S. Typhimurium and E. coli in carrot juice during cold storage, but it was ineffective at inhibiting the growth of L. monocytogenes. There was a risk of foodborne illness despite the low-temperature storage of juice. The innovation of this preliminary study is to find the impact of high pressure on the inactivate kinetics of three food pathogens in carrot juice and its practical application in simulated contaminated juice.

CEO cultural background and overinvestment decisions: The north-south divide in China.

This study addresses an under-researched area in corporate behavior by examining the impact of a CEO's cultural background on corporate overinvestment decisions. We focus on the unique cultural dichotomy between northern and southern China as our context of study. Additionally, we scrutinize the interactions between a CEO's age and the type of company ownership in influencing overinvestment tendencies. Our aim is to enrich theoretical understanding of factors influencing corporate overinvestment, offering practical implications for businesses within and beyond China. By filling this gap in the literature, our study sheds light on the nuanced determinants of overinvestment decisions, aiding businesses in refining their investment strategies and governance mechanisms.

Rhodium-Catalyzed Enantioselective Addition of Heteroarenium Salts Enabled by Nucleophilic Cyclization of 2-Alkynylanilines.

Transition-metal-catalyzed cyclative coupling of 2-alkynylanilines provides a feasible routine for accessing functionalized indoles. Herein, a rhodium-catalyzed highly enantioselective addition of heteroarenium salts is presented, which is enabled by the nucleophilic cyclization of 2-alkynylanilines. It offers feasible protocols to access enantioenriched functionalized indoles tethered to 1,2-dihydropyridine and 1,2-dihydroquinoline motifs with excellent enantioselectivities.

Undergraduate nurses' reflections on visual thinking learning to construct inductive reasoning through situated patient pictures: A mixed-method study.

BACKGROUND/OBJECTIVE: Deductive logic has often been used to develop critical thinking. However, inductive logical thinking, essential to care decision-making, has yet to be emphasized. This study aimed to explore visual thinking learning among undergraduate nursing students by asking them to draw situated patient pictures in order to integrate theoretical knowledge and promote inductive logical thinking. METHODS: A mixed-methods research design was used to obtain quantitative and qualitative data from a convenience sample of 100 students. The study was conducted in a Taiwanese university from September 2022 to January 2023. In the quantitative component, learners' views of situated patient pictures were captured based on 15 paired identifiers and two questions: (a) What word should be used in describing the situated patient's picture? (b) How strongly do you feel about the selection? Written feedback was analyzed using qualitative content analysis. RESULTS: Quantitative analysis identified specific, unpretentious, humorous, harmonious, conservative, realistic, rational, entire, image performance, professional performance, understandable, expressive, static performance, rigorous, and profuse with a reasonable degree of choice. Qualitative analysis identified four stages in participants' development of inductive reasoning through situated patient pictures and visual thinking learning. These were: exploration, intuition, theme, and logic and creation. CONCLUSIONS: The results suggest that visual thinking learning is a practical pedagogical approach to increasing learners' communication abilities, group cooperation, theoretical knowledge integration, and logical thinking. Neither educators nor learners required any artistic skills. Nonetheless, participants demonstrated creativity and innovation through continuous visual thinking learning.

A Cell Surface-Binding Antibody Atlas Nominates a MUC18-Directed Antibody-Drug Conjugate for Targeting Melanoma.

Recent advances in targeted therapy and immunotherapy have substantially improved the treatment of melanoma. However, therapeutic strategies are still needed for unresponsive or treatment-relapsed patients with melanoma. To discover antibody-drug conjugate (ADC)-tractable cell surface targets for melanoma, we developed an atlas of melanoma cell surface-binding antibodies (pAb) using a proteome-scale antibody array platform. Target identification of pAbs led to development of melanoma cell killing ADCs against LGR6, TRPM1, ASAP1, and MUC18, among others. MUC18 was overexpressed in both tumor cells and tumor-infiltrating blood vessels across major melanoma subtypes, making it a potential dual-compartment and universal melanoma therapeutic target. AMT-253, an MUC18-directed ADC based on topoisomerase I inhibitor exatecan and a self-immolative T moiety, had a higher therapeutic index compared with its microtubule inhibitor-based counterpart and favorable pharmacokinetics and tolerability in monkeys. AMT-253 exhibited MUC18-specific cytotoxicity through DNA damage and apoptosis and a strong bystander killing effect, leading to potent antitumor activities against melanoma cell line and patient-derived xenograft models. Tumor vasculature targeting by a mouse MUC18-specific antibody-T1000-exatecan conjugate inhibited tumor growth in human melanoma xenografts. Combination therapy of AMT-253 with an antiangiogenic agent generated higher efficacy than single agent in a mucosal melanoma model. Beyond melanoma, AMT-253 was also efficacious in a wide range of MUC18-expressing solid tumors. Efficient target/antibody discovery in combination with the T moiety-exatecan linker-payload exemplified here may facilitate discovery of new ADC to improve cancer treatment. SIGNIFICANCE: Discovery of melanoma-targeting antibodies using a proteome-scale array and use of a cutting-edge linker-payload system led to development of a MUC18-targeting antibody-exatecan conjugate with clinical potential for treating major melanoma subtypes.

HSP90 C-terminal domain inhibition promotes VDAC1 oligomerization via decreasing K274 mono-ubiquitination in Hepatocellular Carcinoma.

Voltage-dependent anion-selective channel protein 1 (VDAC1) is the most abundant protein in the mitochondrial outer membrane and plays a crucial role in the control of hepatocellular carcinoma (HCC) progress. Our previous research found that cytosolic molecular chaperone heat shock protein 90 (Hsp90) interacted with VDAC1, but the effect of the C-terminal and N-terminal domains of Hsp90 on the formation of VDAC1 oligomers is unclear. In this study, we focused on the effect of the C-terminal domain of Hsp90 on VDAC1 oligomerization, ubiquitination, and VDAC1 channel activity. We found that Hsp90 C-terminal domain inhibitor Novobiocin promoted VDAC1 oligomerization, release of cytochrome c, and activated mitochondrial apoptosis pathway. Atomic coarse particle modeling simulation revealed C-terminal domain of Hsp90α stabilized VDAC1 monomers. The purified VDAC1 was reconstituted into a planar lipid bilayer, and electrophysiology experiments of patch clamp showed that the Hsp90 C-terminal inhibitor Novobiocin increased VDAC1 channel conductance via promoting VDAC1 oligomerization. The mitochondrial ubiquitination proteomics results showed that VDAC1 K274 mono-ubiquitination was significantly decreased upon Novobiocin treatment. Site-directed mutation of VDAC1 (K274R) weakened Hsp90α-VDAC1 interaction and increased VDAC1 oligomerization. Taken together, our results reveal that Hsp90 C-terminal domain inhibition promotes VDAC1 oligomerization and VDAC1 channel conductance by decreasing VDAC1 K274 mono- ubiquitination, which provides a new perspective for mitochondria-targeted therapy of HCC.

Tai Chi as a complementary exercise for pulmonary rehabilitation in chronic obstructive pulmonary disease: A randomised controlled trial.

OBJECTIVES: With the characteristics of mindfulness and breathing techniques, Tai Chi has been recommended with therapeutic values in chronic obstructive pulmonary disease (COPD). However, its strengths as a complementary exercise for conventional pulmonary rehabilitation (PR) remain unclear. DESIGN AND SETTING: This single-blinded randomised controlled trial recruited patients with mild to severe stable COPD. Eligible participants were randomly assigned to the group with usual care (control), total body recumbent stepper (TBRS) exercise, Tai Chi (TC), or combined TBRS exercise and Tai Chi (TBRS-TC). Patients received a two-month hospital-based supervised exercise, followed by a ten-month community- or home-based rehabilitation program. RESULTS: A total of 120 participants were recruited, and 102 were included in the per-protocol analysis. The mean changes in St George's Respiratory Questionnaire (SGRQ) total score from baseline to the post-hospital exercise in the control group, TBRS group, TC group, and TBRS-TC group was 2.62 (95 % CI -8.99 to 8.99), -9.28 (95 % CI -13.96 to -4.60), -10.19 (95 % CI -13.72 to -6.67), and -16.75 (95 % CI -20.25 to -13.24), respectively, with a statistically significant difference between groups in favor of the TBRS-TC exercise (P < 0.001). The remarkable effect of TBRS-TC exercise in improving the quality of life maintained until the end of the community- or home-based rehabilitation training (P < 0.001). Besides, a statistically better effect with the TBRS-TC exercise was also observed in the outcomes regarding exercise capacity, pulmonary function, symptom burden, and systemic inflammation after the whole process of 12-month integrative PR exercise programme. CONCLUSIONS: Based on the results, a novel integrated exercise modality combining Tai Chi and conventional pulmonary rehabilitation was developed. It might contribute to more positive effects in patients with stable COPD. REGISTRATION: The study was registered with the Chinese Clinical Trial Registry (ChiCTR-IOR-15006874) prior to commencing recruitment.