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The microgeometry of the cellular microenvironment profoundly impacts cellular behaviors, yet the link between it and the ubiquitously expressed mechanosensitive ion channel PIEZO1 remains unclear. Herein, we describe a fluorescent micropipette aspiration assay that allows for simultaneous visualization of intracellular calcium dynamics and cytoskeletal architecture in real-time, under varied micropipette geometries. By integrating elastic shell finite element analysis with fluorescent lifetime imaging microscopy and employing PIEZO1-specific transgenic red blood cells and HEK cell lines, we demonstrate a direct correlation between the microscale geometry of aspiration and PIEZO1-mediated calcium signaling. We reveal that increased micropipette tip angles and physical constrictions lead to a significant reorganization of F-actin, accumulation at the aspirated cell neck, and subsequently amplify the tension stress at the dome of the cell to induce more PIEZO1’s activity. Disruption of the F-actin network or inhibition of its mobility leads to a notable decline in PIEZO1 mediated calcium influx, underscoring its critical role in cellular mechanosensing amidst geometrical constraints. Cells sense mechanical force through PIEZO1 channels. Here, authors show that both microgeometry and aspiration force mediate the PIEZO1 activity, and also alter F-actin organization, further amplifying PIEZO1 activity along membrane.

Cancer cells interacting with the extracellular matrix (ECM) in the tumor microenvironment is pivotal for tumorigenesis, invasion, and metastasis. Cell–ECM adhesion has been intensively studied in cancer biology in the past decades to understand the molecular mechanisms underlying the adhesion events and extracellular mechanosensing, as well as develop therapeutic strategies targeting the cell adhesion molecules. Many methods have been established to measure the cell–ECM adhesion strength and correlate it with the metastatic potential of certain cancer types. However, those approaches are either low throughput, not quantitative, or with poor sensitivity and reproducibility. Herein, we developed a novel acoustic force spectroscopy based method to quantify the cell–ECM adhesion strength during adhesion maturation process using the emerging z-Movi® technology. This can be served as a fast, simple, and high-throughput platform for functional assessment of cell adhesion molecules in a highly predictive and reproducible manner.

Vaccines are highly effective in preventing the spread of communicable diseases and are critical to overall public health. As immune stimulants vaccine adjuvants augment the level and longevity of these protective responses. Seeking novel adjuvants using parallel high throughput screens and subsequent systematic structure-activity relationship studies we identified an analogue of a hit compound, , that in screening assays retained induction of calcium (Ca ) influx, tetraspanin CD63 EV reporter activity and cell viability. Here, we further our analyses of the biological activity of related its potential use as a vaccine adjuvant. was tested for activation of murine bone marrow-derived dendritic cells (mBMDC) by flow cytometry for Ca entry, levels of CD80 and CD86 expression, and stimulation of antigen-specific T cell proliferation. Cytokines and IgG responses from BALB/c mice injected with as a single agent or as an adjuvant with ovalbumen were measured by ELISA. triggered store-operated Ca entry in mBMDC as well as increases in CD80 and CD86 surface expression. In co-culture experiments, this compound amplified the stimulation of cognate T cell proliferation. Intramuscular injection of elicited minimal systemic cytokine and chemokine release. When used as an adjuvant with ovalbumen, generated a significant antigen-specific IgG1 response with a higher splenocyte T helper 2 (Th2) cytokine response. activated mBMDCs associated with EV release and a store-operated calcium entry response. Enhanced cognate T cell proliferation was mediated either through direct engagement with compound-stimulated mBMDCs or indirectly via immunostimulatory extracellular vesicles released by -activated mBMDCs. elicited minimal systemic cytokine and chemokine release, demonstrating a promising safety profile. When used as an adjuvant in a murine vaccination model, enhanced the IgG1 response with an associated T helper 2 cytokine profile. Hence this compound shows promise as an adjuvant if a Th2 response is beneficial or in combination with other agents to provide a balanced immune response in vaccines.

Systemically vaccinated individuals against COVID-19 and influenza may continue to support viral replication and shedding in the upper airways, contributing to the spread of infections. Thus, a vaccine regimen that enhances mucosal immunity in the respiratory mucosa is needed to prevent a pandemic. Intranasal/pulmonary (IN) vaccines can promote mucosal immunity by promoting IgA secretion at the infection site. Here, we demonstrate that an intramuscular (IM) priming-IN boosting regimen with an inactivated influenza A virus adjuvanted with the liposomal dual TLR4/7 adjuvant (Fos47) enhances systemic and local/mucosal immunity. The IN boosting with Fos47 (IN-Fos47) enhanced antigen-specific IgA secretion in the upper and lower respiratory tracts compared to the IM boosting with Fos47 (IM-Fos47). The secreted IgA induced by IN-Fos47 was also cross-reactive to multiple influenza virus strains. Antigen-specific tissue-resident memory T cells in the lung were increased after IN boosting with Fos47, indicating that IN-Fos47 established tissue-resident T cells. Furthermore, IN-Fos47 induced systemic cross-reactive IgG antibody titers comparable to those of IM-Fos47. Neither local nor systemic reactogenicity or adverse effects were observed after IN delivery of Fos47. Collectively, these results indicate that the IM/IN regimen with Fos47 is safe and provides both local and systemic anti-influenza immune responses.

Despite the clinical efficacy of current intramuscular influenza vaccines in reducing the severity of seasonal infection, they exhibit limited induction of mucosal immunity, which is essential for preventing viral transmission. In addition, intranasal vaccination can induce superior mucosal immunity, enhancing clinical efficacy and reducing transmission, and its self-boosting potential may improve coverage in older adults and those with mobility limitations. We developed Lipo-1V270, a liposomal nanoparticle formulation of the synthetic TLR7 agonist 1V270 using 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and cholesterol for mucosal vaccine delivery. In vitro immune stimulation and in vivo immunogenicity were evaluated using intramuscular and intranasal routes in mouse models, including a heterologous prime-boost regimen with inactivated influenza A virus [IIAV, A/California/04/2009 (H1N1)pdm09] adjuvanted monophosphoryl lipid A (MPLA) priming. In vitro analysis showed that Lipo-1V270 exhibited attenuated innate immune potency compared to unformulated 1V270. However, in vivo co-administration of Lipo-1V270 with IIAV significantly enhanced antigen-specific IgG1 and IgG2a responses. Subsequently, intranasal boosting with Lipo-1V270, following intramuscular priming with IIAV adjuvanted with MPLA - a component included in FDA-approved vaccines - elicited robust influenza-hemagglutinin (HA)-specific mucosal IgA and IgG responses in nasal wash. This heterologous prime-boost regimen also induced strong splenic T-cell responses and HA-specific IgG and IgA antibodies in nasal wash without causing significant weight loss for 7 days post-boost in immunized mice. Intranasal administration of Lipo-1V270 in a heterologous prime-boost vaccination regimen effectively enhances mucosal immunity against influenza virus infection, with an acceptable innate immune-mediated adverse effects profile. This strategy may be applicable to vaccines against other respiratory infectious diseases. •Vaccination with inactivated Influenza A virus (IIAV) adjuvanted with liposomal formulation of small molecule TLR7 ligand induced both Th1 and Th2 biased responses.•A heterologous immunization with MPLA prime and intranasal Lipo-1 V270 with IIAV boost strategy improved mucosal anti-influenza immune response.•Vaccination with Lipo-1V270 adjuvanted vaccine did not show immune mediated systemic adverse effects.

Peripheral T-cell lymphomas are aggressive non-Hodgkin lymphomas with few treatment options for relapsed or refractory disease. Valemetostat tosylate (valemetostat) is a potent, novel, dual inhibitor of EZH2 and EZH1. We investigated the clinical activity and safety of valemetostat in patients with relapsed or refractory peripheral T-cell lymphoma, and its safety in patients with relapsed or refractory adult T-cell leukaemia/lymphoma. VALENTINE-PTCL01 was a multicentre, open-label, single-arm, phase 2 trial performed at 47 hospitals in 12 countries across Asia, Europe, North America, and Oceania. Patients with either peripheral T-cell lymphoma or adult T-cell leukaemia/lymphoma, aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–2 received oral valemetostat at 200 mg per day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint for patients with peripheral T-cell lymphoma was the CT-based objective response rate by blinded independent central review (BICR) using 2014 Lugano response criteria. Patients who received valemetostat and had a confirmed eligible peripheral T-cell lymphoma subtype on central review were included in the efficacy analysis. The primary endpoint for patients with adult T-cell leukaemia/lymphoma was the safety and tolerability of valemetostat. Safety in both cohorts was assessed in all patients who received at least one dose of valemetostat. The trial is registered with ClinicalTrials.gov, NCT04703192, and EudraCT, 2020-004954-31, and is closed to enrolment. Between June 16, 2021, and Aug 10, 2022, 133 patients with relapsed or refractory peripheral T-cell lymphoma (median age 69·0 years [IQR 58·0–74·0]; 91 [68%] were male, and 42 [32%] were female) and 22 patients with adult T-cell leukaemia/lymphoma (66·5 years [54·0–73·0]; 15 [68%] were male, and seven [32%] were female) were enrolled. The median follow-up time was 12·3 months (95% CI 11·8–13·8). 52 (44%; 95% CI 35–53) of 119 efficacy-evaluable patients with relapsed or refractory peripheral T-cell lymphoma had an objective response. The most common grade 3−4 adverse events were thrombocytopenia (31 [23%] of 133 patients in the peripheral T-cell lymphoma group and 11 [50%] of 22 patients in the adult T-cell leukaemia/lymphoma group), anaemia (25 [19%] and ten [46%]), and neutropenia (23 [17%] and four [18%]). Serious treatment-emergent adverse events were reported in 53 (40%) patients with peripheral T-cell lymphoma and 15 (68%) patients with adult T-cell leukaemia/lymphoma; nine (7%) patients and one (5%) patient had a serious treatment-emergent adverse event considered to be treatment related, respectively. No treatment-related deaths were reported. These data show that treatment with valemetostat leads to durable responses in patients with relapsed or refractory peripheral T-cell lymphoma, with a manageable safety profile. Daiichi Sankyo.

Breast cancer (BC) in the Asia Pacific regions is enriched in younger patients and rapidly rising in incidence yet its molecular bases remain poorly characterized. Here we analyze the whole exomes and transcriptomes of 187 primary tumors from a Korean BC cohort (SMC) enriched in pre-menopausal patients and perform systematic comparison with a primarily Caucasian and post-menopausal BC cohort (TCGA). SMC harbors higher proportions of HER2+ and Luminal B subtypes, lower proportion of Luminal A with decreased ESR1 expression compared to TCGA. We also observe increased mutation prevalence affecting BRCA1 , BRCA2 , and TP53 in SMC with an enrichment of a mutation signature linked to homologous recombination repair deficiency in TNBC. Finally, virtual microdissection and multivariate analyses reveal that Korean BC status is independently associated with increased TIL and decreased TGF-β signaling expression signatures, suggesting that younger Asian BCs harbor more immune-active microenvironment than western BCs. While breast cancer incidence in the Asia Pacific region is rising, the molecular basis remains poorly characterized. Here the authors perform genomic screening of 187 Korean breast cancer patients and find differences in molecular subtype distribution, mutation pattern and prevalence, and gene expression signature when compared to TCGA.

To quantify the impacts of tides on seaside operations in container ports, this study reformulates the berth allocation problem by modeling their impacts on the entrance/exit of vessels into/from ports. Furthermore, to mitigate the tidal impacts, we borrow the so-called virtual arrival policy, whose potential for reducing bunker fuel consumption and vessel emissions is widely recognized by the shipping industry, and accordingly retrofit the berth allocation model. In the latter model, the state-of-the-art technique of second-order cone programming is adopted to handle the nonlinear intractability involved. We conduct extensive numerical experiments to evaluate the impacts of tides on the seaside operations in a tidal container port, and also to verify the competence of the virtual arrival policy in delivering win–win economic and environmental benefits for both the port and shipping lines. It is also intriguing to observe that the virtual arrival policy would be an applicable substitute for the costly approach of deepening the navigation channel in a tidal port.

Discharge letters are a critical component in the continuity of care between specialists and primary care providers. However, these letters are time-consuming to write, underprioritized in comparison to direct clinical care, and are often tasked to junior doctors. Prior studies assessing the quality of discharge summaries written for inpatient hospital admissions show inadequacies in many domains. Large language models such as GPT have the ability to summarize large volumes of unstructured free text such as electronic medical records and have the potential to automate such tasks, providing time savings and consistency in quality. The aim of this study was to assess the performance of GPT-4 in generating discharge letters written from urology specialist outpatient clinics to primary care providers and to compare their quality against letters written by junior clinicians. Fictional electronic records were written by physicians simulating 5 common urology outpatient cases with long-term follow-up. Records comprised simulated consultation notes, referral letters and replies, and relevant discharge summaries from inpatient admissions. GPT-4 was tasked to write discharge letters for these cases with a specified target audience of primary care providers who would be continuing the patient's care. Prompts were written for safety, content, and style. Concurrently, junior clinicians were provided with the same case records and instructional prompts. GPT-4 output was assessed for instances of hallucination. A blinded panel of primary care physicians then evaluated the letters using a standardized questionnaire tool. GPT-4 outperformed human counterparts in information provision (mean 4.32, SD 0.95 vs 3.70, SD 1.27; P=.03) and had no instances of hallucination. There were no statistically significant differences in the mean clarity (4.16, SD 0.95 vs 3.68, SD 1.24; P=.12), collegiality (4.36, SD 1.00 vs 3.84, SD 1.22; P=.05), conciseness (3.60, SD 1.12 vs 3.64, SD 1.27; P=.71), follow-up recommendations (4.16, SD 1.03 vs 3.72, SD 1.13; P=.08), and overall satisfaction (3.96, SD 1.14 vs 3.62, SD 1.34; P=.36) between the letters generated by GPT-4 and humans, respectively. Discharge letters written by GPT-4 had equivalent quality to those written by junior clinicians, without any hallucinations. This study provides a proof of concept that large language models can be useful and safe tools in clinical documentation.

Enantiopure turbo chirality in small organic molecules, without other chiral elements, is a fascinating topic that has garnered significant interest within the chemical and materials science community. However, further research into and application of this concept have been severely limited by the lack of effective asymmetric tools. To date, only a few enantiomers of turbo chiral targets have been isolated, and these were obtained through physical separation using chiral HPLC, typically on milligram scales. In this work, we report the first asymmetric approach to enantiopure turbo chirality in the absence of other chiral elements such as central and axial chirality. This is demonstrated by assembling aromatic phosphine oxides, where three propeller-like groups are anchored to a P(O) center via three axes. Asymmetric induction was successfully carried out using a chiral sulfonimine auxiliary, with absolute configurations and conformations unambiguously determined by X-ray diffraction analysis. The resulting turbo frameworks exhibit three propellers arranged in either a clockwise (P,P,P) or counterclockwise (M,M,M) configuration. In these arrangements, the bulkier sides of the aromatic rings are oriented toward the oxygen atom of the P=O bond rather than in the opposite direction. Additionally, the orientational configuration is controlled by the sulfonimine auxiliary as well, showing that one of the Naph rings is pushed away from the auxiliary group (-CH2-NHSO2-tBu) of the phenyl ring. Computational studies were conducted on relative energies for the rotational barriers of a turbo target along the P=O axis and the transition pathway between two enantiomers, meeting our expectations. This work is expected to have a significant impact on the fields of chemistry, biomedicine, and materials science in the future.