RNA Sequencing Analysis of Monocytes Exposed to Airway Fluid From Children With Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: Monocytes are plastic cells that assume different polarization states that can either promote inflammation or tissue repair and inflammation resolution. Polarized monocytes are partially defined by their transcriptional profiles that are influenced by environmental stimuli. The airway monocyte response in pediatric acute respiratory distress syndrome (PARDS) is undefined. To identify differentially expressed genes and networks using a novel transcriptomic reporter assay with donor monocytes exposed to the airway fluid of intubated children with and at-risk for PARDS. To determine differences in gene expression at two time points using the donor monocyte assay exposed to airway fluid from intubated children with PARDS obtained 48-96 hours following initial tracheal aspirate sampling. DESIGN: In vitro pilot study carried out using airway fluid supernatant. SETTING: Academic 40-bed PICU. PARTICIPANTS: Fifty-seven children: 44 children with PARDS and 13 children at-risk for PARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We performed bulk RNA sequencing using a transcriptomic reporter assay of monocytes exposed to airway fluid from intubated children to discover gene networks differentiating PARDS from at-risk for PARDS and those differentiating mild/moderate from severe PARDS. We also report differences in gene expression in children with PARDS 48-96 hours following initial tracheal aspirate sampling. We found that interleukin (IL)-10, IL-4, and IL-13, cytokine/chemokine signaling, and the senescence-associated secretory phenotype are upregulated in monocytes exposed to airway fluid from intubated children with PARDS compared with those at-risk for PARDS. Signaling by NOTCH, histone deacetylation/acetylation, DNA methylation, chromatin modifications (B-WICH complex), and RNA polymerase I transcription and its associated regulatory apparatus were upregulated in children with PARDS 48-96 hours following initial tracheal aspirate sampling. CONCLUSIONS: We identified gene networks important to the PARDS airway immune response using bulk RNA sequencing from a monocyte reporter assay that exposed monocytes to airway fluid from intubated children with and at-risk for PARDS. Mechanistic investigations are needed to validate our findings.

The branched N-glycan of PD-L1 predicts immunotherapy responses in patients with recurrent/metastatic HNSCC.

Immunotherapy has revolutionized cancer treatment, but the lack of a reliable predictive biomarker for treatment response remains a challenge. Alpha-1,6-Mannosylglycoprotein 6-ß-N-Acetylglucosaminyltransferase 5 (MGAT5) is a key regulator of complex N-glycan synthesis, and its dysregulation is associated with cancer progression. The lectin Phaseolus vulgaris leukoagglutinin (PHA-L) specifically binds to mature MGAT5 products. Previous studies have indicated elevated PHA-L staining in head and neck squamous cell carcinoma (HNSCC), which implies increased activity of MGAT5. However, the specific role of MGAT5 in HNSCC remains unclear. In this study, we found significantly higher PHA-L staining and MGAT5 expression in HNSCC tumors compared to adjacent non-tumor tissues. Using a mass spectrometry (MS)-based glycoproteomic approach, we identified 163 potential protein substrates of MGAT5. Functional analysis revealed that protein substrates of MGAT5 regulated pathways related to T cell proliferation and activation. We further discovered that PD-L1 was among the protein substrates of MGAT5, and the expression of MGAT5 protected tumor cells from cytotoxic T lymphocyte (CTL) killing. Treatment of nivolumab alleviated the protective effects of MGAT5 on CTL activity. Consistently, patients with MGAT5-positive tumors showed improved responses to immunotherapy compared to those with MGAT5-negative tumors. Using purified PD-L1 from HNSCC cells and a glycoproteomic approach, we further deciphered that the N35 and N200 sites carry the majority of complex N-glycans on PD-L1. Our findings highlight the critical role of MGAT5-mediated branched N-glycans on PD-L1 in modulating the interaction with the immune checkpoint receptor PD-1. Consequently, we propose that MGAT5 could serve as a biomarker to predict patients' responses to anti-PD-1 therapy. Furthermore, targeting the branched N-glycans at N35 and N200 of PD-L1 may lead to the development of novel diagnostic and therapeutic approaches.

Bacterial consortium amendment effectively reduces Pb/Cd bioavailability in soil and their accumulation in wheat.

Microbial remediation can maintain the sustainability of farmlands contaminated with heavy metals (HMs). However, the effects of bacterial consortium on crop growth and potential risks under HM stress, as well as its mechanisms, are still unclear compared with a single microorganism. Here, we investigated the effect of a bacterial consortium consisting of some HMs-resistant bacteria, including Bacillus cereus, Bacillus thuringiensis, and Herbaspirillum huttiense, on plant growth promotion and inhibition of Pb/Cd accumulation within different contaminated soil-wheat systems through pot experiments. The results showed that microbial inoculation alleviated HMs-induced growth inhibition by activating antioxidant enzymes and inhibiting lipid peroxidation, and enhanced plant growth in the bacterial consortium. Compared to a single strain (Bacillus cereus, Bacillus thuringiensis, or Herbaspirillum huttiense), the bacterial consortium was more conducive to improving root development and reducing the content of available HMs in soil (4.5-10.3%) and its transfer to shoot (4.3-8.4%). Moreover, bacterial consortium significantly increased soil enzyme activities and available nutrients, resulting in nearly twice that of a single strain on the effect of soil quality and plant growth. Correlation analysis and least square path analysis showed that the bacterial consortium could significantly reduce the HMs-enrichment/transport from soil to shoot than a single strain by regulating soil available HMs and biochemical properties, as well as the parameters for plant growth. This study emphasizes that bacterial consortium promotes the growth of the crop wheat and reduces the risk of HMs entering human food chain, further providing an effective strategy for the safe production of food crops in contaminated soils.

Long-term antibody response after the third dose of inactivated SARS-CoV-2 vaccine in MASLD patients.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) patients are at an elevated risk of developing severe coronavirus disease 2019 (COVID-19). The objective of this study was to assess antibody responses and safety profiles six months after the third dose of the inactivated acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in MASLD patients. METHODS: This study included MASLD patients and healthy volunteers without a history of SARS-CoV-2 infection. Blood samples were collected six months after receiving the third dose of the inactivated vaccine to measure the levels of neutralizing antibodies (NAbs) and anti-spike IgG antibodies against SARS-CoV-2. RESULTS: A total of 335 participants (214 MASLD patients and 121 healthy volunteers) were enrolled. The seroprevalence of NAb was 61.7% (132 of 214) in MASLD patients and 74.4% (90 of 121) in healthy volunteers, which was a significant difference (p = 0.018). Statistically significant differences in IgG seroprevalence were also observed between MASLD patients and healthy volunteers (p = 0.004). Multivariate analysis demonstrated that the severity of MASLD (OR, 2.97; 95% CI, 1.32-6.68; p = 0.009) and age (OR, 1.03; 95% CI, 1.01-1.06; p = 0.004) were independent risk factors for NAb negativity in MASLD patients. Moderate/severe MASLD patients had a lower NAb seroprevalence than mild MASLD patients (45.0% vs. 65.5%, p = 0.016). CONCLUSION: Lower antibody responses were observed in MASLD patients six months after their third dose of the inactivated vaccine than in healthy volunteers, providing further assistance in monitoring patients who are more vulnerable to hypo-responsiveness to SARS-CoV-2 vaccines.

In vivo CRISPR screens identify Mga as an immunotherapy target in triple-negative breast cancer.

Immune evasion is not only critical for tumor initiation and progression, but also determines the efficacy of immunotherapies. Through iterative in vivo CRISPR screens with seven syngeneic tumor models, we identified core and context-dependent immune evasion pathways across cancer types. This valuable high-confidence dataset is available for the further understanding of tumor intrinsic immunomodulators, which may lead to the discovery of effective anticancer therapeutic targets. With a focus on triple-negative breast cancer (TNBC), we found that Mga knock-out significantly enhances antitumor immunity and inhibits tumor growth. Transcriptomics and single-cell RNA sequencing analyses revealed that Mga influences various immune-related pathways in the tumor microenvironment. Our findings suggest that Mga may play a role in modulating the tumor immune landscape, though the precise mechanisms require further investigation. Interestingly, we observed that low MGA expression in breast cancer patients correlates with a favorable prognosis, particularly in those with active interferon-γ signaling. These observations provide insights into tumor immune escape mechanisms and suggest that further exploration of MGA's function could potentially lead to effective therapeutic strategies in TNBC.

Sports tourism downturn: The impact of COVID-19 on Chinese tourism among urban and rural residents under epidemic.

BACKGROUND: China's sports tourism has seen significant growth since the 2008 Olympics, only to be challenged by the coronavirus disease 2019 pandemic. This study aims to assess the impact of the pandemic on China's tourism and sports tourism, which are highly interrelated. METHOD: Data and materials from 2019 to mid-2023 were systematically collected and analyzed, focusing on seasonal tourism reports published on official local networks in China. RESULTS: The study reveals a prepandemic annual tourism consumption of 6.63 trillion CNY, a 52.1% decline during the pandemic, and a postpandemic rebound exceeding pre-coronavirus disease levels. CONCLUSION: The pandemic's impact was profound, yet the resilience of China's tourism sector is evident, with a focus on the recovery's implications for sustainable growth. Despite the pandemic's disruption, China's tourism and sports tourism sectors have demonstrated resilience and potential for continued growth, warranting ongoing attention.

Genotype and phenotype analysis of α-thalassemia fusion gene in southern China.

OBJECTIVE: The α-globin fusion gene between the HBA2 and HBAP1 genes, is clinically important in thalassemia screening because this fusion gene can cause severe hemoglobin (Hb) H disease when combined with α0 -thalassemia (α0 -thal). In this study, we evaluate the red blood cell parameters of α-thalassemia fusion gene in southern China. METHOD: Study samples suspected of α-thalassemia fusion gene were collected and confirmed by PCR-sequencing from one medical lab center in southern China. Their genotypes and phenotypes were analyzed. RESULTS: A total of 266 cases of α-thalassemia fusion gene were confirmed in our lab from 2017 to 2023, most of them were from Hainan province (169 cases) and Huadu district of Guangzhou (21 cases), the nationality of 143 cases from Hainan was identified, with 71.3% (102/143) being from the Li minority. The Hb, MCV, MCH for αα/(αα)fusion in adult males were 143.5±11.83g/L, 81.51±4.39 fl, and 26.26±1.29 pg, respectively; and in females, they were 126.69±12.89 g/L, 80.10±4.05 fl, 25.8±2.04 pg, respectively. All 12 cases (αα) Fusion/ --SEA showed anemia with decreased Hb, MCV and MCH. CONCLUSION: The carriers of α-globin fusion gene heterozygotes are clinically silent and exhibit an α+ phenotype. Individuals with (αα)Fusion/--SEA show apparent anemia. This α-globin fusion gene is relatively common in southern China, specifically among the Li minority of Hainan province. Therefore, it should be taken into account for genetic counseling purposes.

MEF2A, a gene associated with mitochondrial biogenesis, promotes drug resistance in gastric cancer.

Chemotherapeutic resistance is a major obstacle to the effectiveness of cisplatin-based chemotherapy for gastric cancer (GC), leading to treatment failure and poor survival rates. However, the underlying mechanisms are not fully understood. Our study demonstrated that the transcription factor myocyte enhancer factor 2A (MEF2A) plays a role in chemotherapeutic drug resistance by regulating the transcription of PGC1α and KEAP1, promoting mitochondrial biogenesis. It was found that increased MEF2A expression is linked with poor prognosis, cisplatin insensitivity, and mitochondrial function in GC. MEF2A overexpression significantly decreases GC cell sensitivity in vitro and in vivo, while MEF2A knockdown enhances the sensitivity to cisplatin. Mechanistically, MEF2A activates the transcription of PGC1α, leading to increased mitochondrial biogenesis. In addition, MEF2A inhibits KEAP1 transcription, reduces NRF2 ubiquitination degradation, and activates the KEAP1/NRF2 signaling pathway, which modulates the reactive oxygen species level. The present study identifies MEF2A as a new critical oncogene involved in GC chemoresistance, suggesting a novel therapeutic target for GC.

Preparation of fern root resistant starch by pullulanase and glucoamylase combined with autoclaving-enzymatic method: physicochemical properties and structural characterization.

BACKGROUND: Fern root starch has a high percentage of amylose and has great potential for application in the field of slow-digesting foods. Clarifying the effect of treatment conditions on fern root starch is key to achieving industrialized production of fern root resistant starch. In the present study, fern root starch was treated by the autoclave-enzymatic method with pullulanase, glucoamylase and mixed enzyme. RESULTS: The content of resistant starch in fern roots treated with mixed enzyme was the highest (24.07 ± 1.11%), which was approximately 320% times that of the native starch, had the best water-holding capacity (151.08%), vital transparency and freeze-thaw stability. By contrast, the solubility, swelling and viscosity were lower than natural starch. In addition, mixed enzyme shows a denser structure, and the crystal form changes from C-type to V-type, with a high relative crystallinity and significantly enhanced thermal stability. CONCLUSION: After mixed enzyme combined with autoclave treatment, the content of resistant starch in fern root was greatly increased. The modified starch molecules did not produce new functional groups, which made the crystal structure of starch molecules more compact, and resistance to enzymatic hydrolysis and high temperature thermal stability were significantly enhanced. This provides a positive reference for further in-depth study of fern root starch, improvement of utilization value, development and innovation of new food health products, and diabetes treatment. © 2024 Society of Chemical Industry.

An epigenetically mediated double negative cascade from EFD to HB21 regulates anther development.

Epigenetic modifications are crucial for plant development. EFD (Exine Formation Defect) encodes a SAM-dependent methyltransferase that is essential for the pollen wall pattern formation and male fertility in Arabidopsis. In this study, we find that the expression of DRM2, a de novo DNA methyltransferase in plants, complements for the defects in efd, suggesting its potential de novo DNA methyltransferase activity. Genetic analysis indicates that EFD functions through HB21, as the knockout of HB21 fully restores fertility in efd mutants. DNA methylation and histone modification analyses reveal that EFD represses the transcription of HB21 through epigenetic mechanisms. Additionally, we demonstrate that HB21 directly represses the expression of genes crucial for pollen formation and anther dehiscence, including CalS5, RPG1/SWEET8, CYP703A2 and NST2. Collectively, our findings unveil a double negative regulatory cascade mediated by epigenetic modifications that coordinates anther development, offering insights into the epigenetic regulation of this process.

Cost-effectiveness analysis of immune checkpoint inhibitors as first-line therapy in advanced biliary tract cancer.

Aim: To assess the cost-effectiveness of immune checkpoint inhibitors as first-line treatments for advanced biliary tract cancer (BTC).Methods: This pharmacoeconomic evaluation employed the fractional polynomial network meta-analysis and partitioned survival model. Costs and utilities were collected from the literature and databases. Sensitivity analyses were used to examine uncertainties.Results: The incremental cost-effectiveness ratios (ICERs) of first-line treatment strategies were $761,371.37 per quality-adjusted life-year (QALY) or $206,222.53/QALY in the US and $354,678.79 /QALY or $213,874.22/QALY in China, respectively. The sensitivity analysis results were largely consistent with the base case.Conclusion: From the US and Chinese payer perspectives, adding durvalumab or pembrolizumab to chemotherapy is unlikely to be cost effective in the first-line setting for advanced BTC.

[Box: see text].

Spatiotemporal evolution of land use efficiency in 357 cities across mainland China from 2000 to 2020 based on SDG 11.3.1.

High-efficiency land use facilitates the maximization of land utilization, lowers urban construction costs, and optimizes urban functional patterns. The Sustainable Development Goal 11.3.1 (SDG 11.3.1) can be used to assess land use efficiency (LUE), understand the current state of land use, and identify the potential for optimization. This study combines SDG 11.3.1 with other supplementary indicators to establish a land use efficiency evaluation system. This system provides a more precise understanding of internal city changes and enables a scientific assessment of urban LUE in Mainland China. The results showed that: (1) A significant number of cities were growing cities, particularly in the eastern region, with the population of built-up areas increased by 2.92 times from 2000 to 2020; (2) From 2000 to 2020, cities in China underwent rapid urban expansion, with the most significant urban expansion index in 2015-2020; (3) The coordination between population growth rate (PGR) and land consumption rate (LCR) worsened in the western region, while the central and eastern regions showed better coordination. (4) As the urban expansion index increased, the compactness index of the cities in the above three regions decreased and were at lower levels. This study establishes an evaluation system to assess the LUE and reveals the spatial and temporal characteristics of urban and population change. It holds paramount significance in enhancing LUE and encouraging sustainable development in Mainland China and serves as a valuable reference for global urban management.

Stage IV non-small cell lung cancer with multiple metastases to the small intestine leading to intussusception: A case report.

BACKGROUND: Gastrointestinal tract metastasis from lung cancer is rare and compared to small cell lung cancer (SCLC), non-SCLC (NSCLC) is even less likely to metastasize in this manner. Additionally, small intestinal tumors can also present with diverse complications, some of which require urgent intervention. CASE SUMMARY: In this report, we detail a unique case of stage IV lung cancer, where the presence of small intestine tumors led to intussusception. Subsequent to a small intestine resection, pathology confirmed that all three tumors within the small intestine were metastases from adenocarcinoma of the lung. The postoperative follow-up period extended beyond 14 mo. CONCLUSION: In patients with stage IV NSCLC, local tumor control can be achieved with various treatments. However, if small intestinal metastasis occurs, surgical intervention remains necessary, as it may improve survival.

Epigallocatechin-3-Gallate Inhibits Oxidative Stress Through the Keap1/Nrf2 Signaling Pathway to Improve Alzheimer Disease.

Alzheimer disease (AD) is a common neurodegenerative disease with an intricate pathophysiological mechanism. Oxidative stress has been shown in several investigations as a significant factor in AD progression. For instance, studies have confirmed that oxidative stress inhibition may considerably improve AD symptoms, with potent antioxidants being touted as a possible interventional strategy in the search for AD treatment. Epigallocatechin-3-gallate (EGCG) acts as a natural catechin that has antioxidant effect. It activates the kelch-like epichlorohydrin-associated proteins (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway to inhibit oxidative stress. The Keap1/Nrf2 signal pathway is not only an upstream signaling target for a variety of antioxidant enzymes, but also minimizes high levels of reactive oxygen species. This report analyzes the antioxidant effect of EGCG in AD, elaborates its specific mechanism of action, and provides a theoretical basis for its clinical application in AD.

Application value of multi-parameter magnetic resonance image-transrectal ultrasound cognitive fusion in prostate biopsy.

Objective: To investigate the effect of three-dimensional (3D) reconstruction-assisted cognitive fusion in targeted prostate biopsy. Results: There was no significant difference in the detection rate of prostate cancer (PCa) between targeted biopsy and systematic biopsy, and there was significant difference in the detection rate of clinically significant prostate cancer (csPCa) between targeted biopsy and systematic biopsy. In the low prostate total specific antigen (tPSA) group, there was no statistically significant difference in the detection rate of prostate cancer between the two biopsy modalities. However, compared with systematic puncture, targeted puncture had a higher detection rate for csPCa and a lower detection rate for clinically insignificant prostate cancer (ciPCa), and the difference was statistically significant. In the high tPSA group, there was no significant difference in the detection rate of PCa, csPCa, and ciPCa between the two biopsy types. Single needle positive rate of targeted puncture (29.77%) was significantly higher than that of systematic puncture (10.28%). Conclusions: The detection rate of csPCa in 3D reconstruction-assisted cognitive fusion targeted prostate biopsy is better than that of 12-needle systematic biopsy, which markedly improved the positive rate of prostate biopsy.

This is the first in-human trial and prospective case series of a novel single-port robotic system for gynaecological surgery: An IDEAL stage 2a study.

BACKGROUND: The Shurui® system (SR-ENS-600) is a novel fully integrated single-port robotic system with bioinspired serpentine surgical manipulators and a camera. METHODS: This was a single-centre prospective case-series study according to the IDEAL stage 2a guidelines to evaluate the feasibility, safety and potential efficacy of the Shurui® system for gynaecological surgeries and to improve the operating process. RESULTS: Ten patients with a gradient of surgical difficulty who had indications for laparoscopic surgery and who volunteered to participate in a clinical trial were enrolled in the study. All 10 subjects successfully completed the procedure without converting to other procedures. No serious complications were reported at the 3-month follow-up. Subjects recover faster after surgery and are highly satisfied with the incision. CONCLUSIONS: Gynaecological single-site laparoscopic surgery with the Shurui® system was technically feasible for well-selected patients with minimal alterations in technique. Further prospective multicenter large-sample studies are necessary. REGISTRATION NUMBER: ChiCTR2300075431. URL: https://www.chictr.org.cn/showproj.html?proj=189995.

Elucidation of the molecular mechanism of type 2 diabetes mellitus affecting the progression of nonalcoholic steatohepatitis using bioinformatics and network pharmacology: A review.

Increasing evidence suggests that patients with diabetes are at increased risk of developing nonalcoholic steatohepatitis (NASH), but the underlying mechanisms that affect the progression of NASH remain unclear. In this study, we used bioinformatics and network pharmacology methods to explore the differentially expressed genes of NASH and the related genes of type 2 diabetes mellitus, and a total of 46 common targets were obtained. Gene ontology showed that the common targets were mainly involved in biological processes such as glucocorticoid, hormone, and bacterium responses. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis signal pathways were mainly in colorectal cancer, amphetamine addition, the peroxisome proliferator-activated receptor signaling pathway, and the toll-like receptor signaling pathway. The protein-protein interaction network identified 8 hub genes, and the co-expression network was analyzed to obtain 7 related functions and mutual proportions of hub genes. A total of 120 transcription factors were predicted for hub genes. Hub genes were closely related to immune cells, including neutropils and eosinophils. In addition, we identified 15 potential candidate drugs based on hub genes that are promising for the treatment of NASH. Type 2 diabetes mellitus can affect the progression of NASH by changing hormone levels and inflammatory responses through multiple targets and signaling pathways. Eight hub genes are expected to be potential targets for subsequent treatment.

Acute effects of eccentric versus concentric exercise on executive function and attention of older adults.

Cognitive function is improved acutely after aerobic and/or resistance exercise, but it is unclear if the types of muscle contraction can influence this effect. This study tested the hypothesis that undertaking an acute bout of exercise with eccentric than concentric contractions would be more beneficial for improving cognitive function post-exercise in older adults. Twenty healthy older adults (66-75y) performed descending stair walking (DSW), ascending stair walking (ASW), and resistance exercise of the knee extensors with eccentric-only (RE-ECC) or concentric-only contractions (RE-CON) for 20 minutes each with a week between exercises in a randomized order. The Stroop tests of color naming (STCN) and conflicting color words (STCC), symbol digit modalities test, digit span test (DST), and two types of the trail making test (TMT-A, TMT-B) were assessed before and after sitting for 20 minutes (control session), and each exercise. A significant (p<0.05) improvement in the baseline test scores was found from the control session to the fourth exercise session. Time to complete the tests was significantly (p<0.05) reduced from pre- to post-exercise as well as after sitting for 20 minutes for STCN (-5.9±7.4s, Cohen's d=0.79), STCC (-8.9±11.1s, d=0.80), TMT-A (-22.6±9.7s, d=2.34) and TMT-B (-23.1±13.7s, d=1.69) without significant difference among the four exercise conditions. A significant (p<0.05) improvement of DST score was found from pre- to post-exercise for DSW (9.0±17.6%, d=0.51) and RE-ECC (6.5±10.6%, d=0.61), but not for ASW and RE-CON. These results partially supported the hypothesis that eccentric exercise could affect acute changes in cognitive function greater than concentric exercise.

Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence.

The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan.

A signal-seeking phase 2 study of Trastuzumab emtansine in tumours harbouring HER2 amplification or mutation.

This single-arm phase II non-randomised trial (ACTRN12619001265167) evaluated trastuzumab emtansine in solid cancers with HER2 amplification or mutation detected by comprehensive genomic profiling. The primary objective was objective response (OR), while secondary objectives included the time to progression (TTP) on study to TTP on prior therapy ratio, progression-free survival (PFS) and overall survival (OS). The cohort included 16 tumours with HER2 mutations (group 1) and 16 with HER2 amplification (group 2). After 17 months median follow-up, ORs occurred in 19% of group 1 (1 salivary gland carcinoma (SGC), 2 lung cancers) and 25% of group 2 (3 SGCs, 1 uterine carcinoma). Fourteen of 29 TTP-evaluable patients achieved a TTP ratio ≥1.3, including 10 without an OR. Median PFS and OS were 4.5 (95% CI 2.1-7.0) and 18.2 months (95% CI 8.1-not reached) respectively. Trastuzumab emtansine showed modest ORs and a favourable change in disease trajectory in select HER2-altered solid cancers.