Oxygen-evolving photosystem II structures during S1-S2-S3 transitions.

Photosystem II (PSII) catalyses the oxidation of water through a four-step cycle of Si states (i = 0-4) at the Mn4CaO5 cluster1-3, during which an extra oxygen (O6) is incorporated at the S3 state to form a possible dioxygen4-7. Structural changes of the metal cluster and its environment during the S-state transitions have been studied on the microsecond timescale. Here we use pump-probe serial femtosecond crystallography to reveal the structural dynamics of PSII from nanoseconds to milliseconds after illumination with one flash (1F) or two flashes (2F). YZ, a tyrosine residue that connects the reaction centre P680 and the Mn4CaO5 cluster, showed structural changes on a nanosecond timescale, as did its surrounding amino acid residues and water molecules, reflecting the fast transfer of electrons and protons after flash illumination. Notably, one water molecule emerged in the vicinity of Glu189 of the D1 subunit of PSII (D1-E189), and was bound to the Ca2+ ion on a sub-microsecond timescale after 2F illumination. This water molecule disappeared later with the concomitant increase of O6, suggesting that it is the origin of O6. We also observed concerted movements of water molecules in the O1, O4 and Cl-1 channels and their surrounding amino acid residues to complete the sequence of electron transfer, proton release and substrate water delivery. These results provide crucial insights into the structural dynamics of PSII during S-state transitions as well as O-O bond formation.

Deficiency of BMAL1 promotes ROS generation and enhances IgE-dependent degranulation in mast cells.

BACKGROUND: Bmal1 (Brain and muscle arnt-like, or Arntl) is a bHLH/PAS domain transcription factor central to the transcription/translation feedback loop of the circadian clock. Mast cells are crucial for effector functions in allergic reaction and their activity follows a circadian rhythm. However, the functional roles of Bmal1 in mast cells remain to be determined. PURPOSE: This study aimed to elucidate the specific roles of Bmal1 in IgE-dependent mast cell degranulation. RESULTS: IgE-dependent degranulation was enhanced in bone marrow-derived mast cells (BMMCs) derived from Bmal1-deficient mice (Bmal1-KO mice) compared to that in BMMCs derived from wild-type mice (WT mice) in the absence of 2-Mercaptoethanol (2-ME) in culture. Mast cell-deficient KitW-sh mice reconstituted with Bmal1-KO BMMCs showed more robust passive cutaneous anaphylactic (PCA) reactions, an in vivo model of IgE-dependent mast cell degranulation, than KitW-sh mice reconstituted with WT BMMCs. In the absence of 2-ME in culture, the mRNA expression of the anti-oxidative genes NF-E2-related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), and heme oxygenase-1 (HO-1) was lower and reactive oxygen species (ROS) generation was higher in Bmal1-KO BMMCs than in WT BMMCs at steady state. The IgE-dependent ROS generation and degranulation were enhanced in Bmal1-KO BMMCs compared to WT BMMCs in the absence of 2-ME in culture. The addition of 2-ME into the culture abrogated or weakened the differences in anti-oxidative gene expression, ROS generation, and IgE-dependent degranulation between WT and Bmal1-KO BMMCs. CONCLUSION: The current findings suggest that Bmal1 controls the expression of anti-oxidative genes in mast cells and Bmal1 deficiency enhanced IgE-dependent degranulation associated with promotion of ROS generation. Thus, Bmal1 may function as a key molecule that integrates redox homeostasis and effector functions in mast cells.

Adaptive response of Pseudomonas aeruginosa under serial ciprofloxacin exposure.

Understanding the evolution of antibiotic resistance is important for combating drug-resistant bacteria. In this work, we investigated the adaptive response of Pseudomonas aeruginosa to ciprofloxacin. Ciprofloxacin-susceptible P. aeruginosa ATCC 9027, CIP-E1 (P. aeruginosa ATCC 9027 exposed to ciprofloxacin for 14 days) and CIP-E2 (CIP-E1 cultured in antibiotic-free broth for 10 days) were compared. Phenotypic responses including cell morphology, antibiotic susceptibility, and production of pyoverdine, pyocyanin and rhamnolipid were assessed. Proteomic responses were evaluated using comparative iTRAQ labelling LC-MS/MS to identify differentially expressed proteins (DEPs). Expression of associated genes coding for notable DEPs and their related regulatory genes were checked using quantitative reverse transcriptase PCR. CIP-E1 displayed a heterogeneous morphology, featuring both filamentous cells and cells with reduced length and width. By contrast, although filaments were not present, CIP-E2 still exhibited size reduction. Considering the MIC values, ciprofloxacin-exposed strains developed resistance to fluoroquinolone antibiotics but maintained susceptibility to other antibiotic classes, except for carbapenems. Pyoverdine and pyocyanin production showed insignificant decreases, whereas there was a significant decrease in rhamnolipid production. A total of 1039 proteins were identified, of which approximately 25 % were DEPs. In general, there were more downregulated proteins than upregulated proteins. Noted changes included decreased OprD and PilP, and increased MexEF-OprN, MvaT and Vfr, as well as proteins of ribosome machinery and metabolism clusters. Gene expression analysis confirmed the proteomic data and indicated the downregulation of rpoB and rpoS. In summary, the response to CIP involved approximately a quarter of the proteome, primarily associated with ribosome machinery and metabolic processes. Potential targets for bacterial interference encompassed outer membrane proteins and global regulators, such as MvaT.

Platelet-rich fibrin as an apical barrier for MTA placement in the treatment of teeth with open apices: a pilot study.

OBJECTIVE: The aim of the present pilot study was to assess the effectiveness of the platelet-rich fibrin (PRF) apical barrier for the placement of MTA for the treatment of teeth with periapical lesions and open apices. METHODS: A total of thirty teeth on twenty-eight patients with open apices and periapical periodontitis were enrolled and divided into two groups in the present pilot study. In the PRF group (fourteen teeth in thirteen patients), nonsurgical endodontic treatment was performed using PRF as an apical matrix, after which the apical plug of the MTA was created. For the non-PRF group (fourteen teeth in fourteen patients), nonsurgical endodontic therapy was performed using only the MTA for an apical plug with no further periapical intervention. Clinical findings and periapical digital radiographs were used for evaluating the healing progress after periodic follow-ups of 1, 3, 6, and 9 months. The horizontal dimension of the periapical lesion was gauged, and the changes in the dimensions were recorded each time. The Friedman test, Dunn-Bonferroni post hoc correction, and Mann-Whitney U test were used for statistical analysis, with P < 0.05 serving as the threshold for determining statistical significance. RESULTS: All patients in both groups in the present pilot study had no clinical symptoms after 1 month, with a significant reduction in the periapical lesion after periodic appointments. The lesion width of the PRF group was significantly smaller than that of the non-PRF group in the sixth and ninth month after treatment. CONCLUSIONS: PRF is a promising apical barrier matrix when combined with MTA for the treatment of teeth with open apices and periapical periodontitis. Small number of study subjects and the short time of follow-up period limit the generalizability of these results. TRIAL REGISTRATION: TCTR, TCTR20221109006. Registered 09 November 2022 - Retrospectively registered, https://www.thaiclinicaltrials.org/show/TCTR20221109006 .

Spatial photoluminescence and lifetime mappings of quasi-2D perovskites coupled with a dielectric metasurface.

Light-matter interaction between quantum emitters and optical cavities plays a vital role in fundamental quantum photonics and the development of optoelectronics. Resonant metasurfaces are proven to be an efficient platform for tailoring the spontaneous emission (SE) of the emitters. In this work, we study the interplay between quasi-2D perovskites and dielectric TiO2 metasurfaces. The metasurface, functioning as an open cavity, enhances electric fields near its plane, thereby influencing the emissions of the perovskite. This is verified through angle-resolved photoluminescence (PL) studies. We also conducted reflectivity measurements and numerical simulations to validate the coupling between the quasi-2D perovskites and photonic modes. Notably, our work introduces a spatial mapping approach to study Purcell enhancement. Using fluorescence lifetime imaging microscopy (FLIM), we directly link the PL and lifetimes of the quasi-2D perovskites in spatial distribution when positioned on the metasurface. This correlation provides unprecedented insights into emitter distribution and emitter-resonator interactions. The methodology opens a new (to the best of our knowledge) approach for studies in quantum optics, optoelectronics, and medical imaging by enabling spatial mapping of both PL intensity and lifetime, differentiating between uncoupled quantum emitters and those coupled with different types of resonators.

Prediction of Food Sensitization in Children with Atopic Dermatitis Based on Disease Severity and Epidermal Layer Impairment.

INTRODUCTION: Atopic dermatitis (AD) is characterized by an impaired epidermal barrier, which could be associated with sensitization to food allergens (FAs) and/or inhaled allergens and contribute to the severity of AD. However, no clinical guidance has been established for evaluations of food sensitization (FS) in AD patients. This study investigated how AD severity and epidermal barrier impairment are associated with FS and factors that can predict FS in children with AD. METHODS: This cross-sectional study included 100 children (12-60 months) diagnosed with AD. AD severity was determined using the Scoring Atopic Dermatitis (SCORAD) index. FS was evaluated by measuring serum-specific IgE antibodies against 31 FAs using an immunoblotting method. Epidermal barrier impairment was assessed by measuring transepidermal water loss (TEWL) and stratum corneum hydration (SCH) levels. RESULTS: 90% of participants were sensitized to at least one tested FA, with cow's milk, egg white, beef, almond, egg yolk, and peanut being the most common. Children with moderate-severe AD had lower SCH levels than those with mild AD. Children with AD who were sensitized to >10 FAs had significantly higher TEWL and lower SCH levels, compared with those sensitized to 1-4 FAs and 5-10 FAs. The SCORAD score and SCH level in lesional skin provided moderately predictive value for sensitization to FAs in children with AD. CONCLUSION: FS is common in children with AD and closely associate with AD severity as well as epidermal barrier impairment. Evaluations of FS should be considered for children with moderate to severe AD and/or low SCH levels.

Review on the Significant Interactions between Ultrafine Gas Bubbles and Biological Systems.

Having sizes comparable with living cells and high abundance, ultrafine bubbles (UBs) are prone to inevitable interactions with different types of cells and facilitate alterations in physiological properties. The interactions of four typical cell types (e.g., bacterial, fungal, plant, and mammalian cells) with UBs have been studied over recent years. For bacterial cells, UBs have been utilized in creating the capillary force to tear down biofilms. The release of high amounts of heat, pressure, and free radicals during bubble rupture is also found to affect bacterial cell growth. Similarly, the bubble gas core identity plays an important role in the development of fungal cells. By the proposed mechanism of attachment of UBs on hydrophobin proteins in the fungal cell wall, oxygen and ozone gas-filled ultrafine bubbles can either promote or hinder the cell growth rate. On the other hand, reactive oxygen species (ROS) formation and mass transfer facilitation are two means of indirect interactions between UBs and plant cells. Likewise, the use of different gas cores in generating bubbles can produce different physical effects on these cells, for example, hydrogen gas for antioxidation against infections and oxygen for oxidation of toxic metal ions. For mammalian cells, the importance of investigating their interactions with UBs lies in the bubbles' action on cell viability as membrane poration for drug delivery can greatly affect cells' survival. UBs have been utilized and tested in forming the pores by different methods, ranging from bubble oscillation and microstream generation through acoustic cavitation to bubble implosion.

Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) study: ultralow prostate-specific antigen decline with apalutamide plus androgen-deprivation therapy.

OBJECTIVE: To assess the association between achievement of prostate-specific antigen (PSA) levels ≤0.2 ng/mL (henceforth 'ultralow') and clinical outcomes in patients in the 'Targeted Investigational Treatment Analysis of Novel Anti-androgen' (TITAN) study (ClinicalTrials.gov Identifier NCT02489318) with metastatic castration-sensitive prostate cancer (mCSPC). PATIENTS AND METHODS: Patients in the TITAN study with mCSPC were randomised to 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy. This post hoc analysis assessed the achievement of a PSA level of 0.2->0.02 ng/mL ('ultralow one' [UL1]) and ≤0.02 ng/mL ('ultralow two' [UL2]) vs >0.2 ng/mL with apalutamide treatment and its association with radiographic progression-free survival (rPFS), overall survival (OS), time to castration-resistant PC (TTCRPC), and time to PSA progression (TTPP). The landmark analysis and Kaplan-Meier methods were used. RESULTS: By 3 months, more patients achieved UL1 and UL2 with apalutamide (38% and 23%) vs placebo (15% and 5%). In the apalutamide-treated patients, UL2 vs PSA >0.2 ng/mL at landmark 3 months was associated with significantly longer rPFS (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.14-0.54), OS (HR 0.24, 95% CI 0.13-0.43), TTCRPC (HR 0.2, 95% CI 0.11-0.38), and TTPP (HR 0.11, 95% CI 0.04-0.27; nominal P values all <0.001); this association was also observed but less pronounced for UL1. Similar findings were observed at 6 months. Early onset of decline to UL2 by 3 months was associated with improved survival vs PSA >0.2 ng/mL anytime (HR 0.12, 95% CI 0.06-0.22; P < 0.001) in apalutamide-treated patients. CONCLUSIONS: In this post hoc analysis of TITAN, patients with the deepest PSA decline derived the greatest benefit. These results extend our findings of apalutamide efficacy in the overall TITAN population, underscoring the clinical value of PSA kinetics as a marker for treatment efficacy. PATIENT SUMMARY: Patients with metastatic prostate cancer that is sensitive to ongoing hormonal treatment benefited significantly from the addition of apalutamide compared with placebo. Those who achieved rapid and deep PSA reduction had the greatest survival benefit.

Inequities in Conversion Practice Exposure at the Intersection of Ethnoracial and Gender Identities.

Objectives. To examine inequities in conversion practice exposure across intersections of ethnoracial groups and gender identity in the United States. Methods. Data were obtained from The Population Research in Identity and Disparities for Equality Study of sexual and gender minority people from 2019 to 2021 (n = 9274). We considered 3 outcomes: lifetime exposure, age of first exposure, and period between first and last exposure among those exposed to conversion practices. We used log-binomial, Cox proportional hazards, and negative binomial models to examine inequities by ethnoracial groups and gender identity adjusting for confounders. We considered additive interaction. Results. Conversion practice prevalence was highest among minoritized ethnoracial transgender and nonbinary participants (TNB; 8.6%). Compared with White cisgender participants, minoritized ethnoracial TNB participants had twice the prevalence (prevalence ratio = 2.16; 95% confidence interval [CI] = 1.62, 2.86) and risk (hazard ratio = 2.04; 95% CI = 1.51, 2.69) of conversion practice exposure. Furthermore, there was evidence of a positive additive interaction for age of first exposure. Conclusions. Minoritized ethnoracial TNB participants were most likely to recall experiencing conversion practices. Public Health Implications. Policies banning conversion practices may reduce the disproportionate burden experienced by minoritized ethnoracial TNB participants. (Am J Public Health. 2024;114(4):424-434. https://doi.org/10.2105/AJPH.2024.307580).

Clinical domain knowledge-derived template improves post hoc AI explanations in pneumothorax classification.

OBJECTIVE: Pneumothorax is an acute thoracic disease caused by abnormal air collection between the lungs and chest wall. Recently, artificial intelligence (AI), especially deep learning (DL), has been increasingly employed for automating the diagnostic process of pneumothorax. To address the opaqueness often associated with DL models, explainable artificial intelligence (XAI) methods have been introduced to outline regions related to pneumothorax. However, these explanations sometimes diverge from actual lesion areas, highlighting the need for further improvement. METHOD: We propose a template-guided approach to incorporate the clinical knowledge of pneumothorax into model explanations generated by XAI methods, thereby enhancing the quality of the explanations. Utilizing one lesion delineation created by radiologists, our approach first generates a template that represents potential areas of pneumothorax occurrence. This template is then superimposed on model explanations to filter out extraneous explanations that fall outside the template's boundaries. To validate its efficacy, we carried out a comparative analysis of three XAI methods (Saliency Map, Grad-CAM, and Integrated Gradients) with and without our template guidance when explaining two DL models (VGG-19 and ResNet-50) in two real-world datasets (SIIM-ACR and ChestX-Det). RESULTS: The proposed approach consistently improved baseline XAI methods across twelve benchmark scenarios built on three XAI methods, two DL models, and two datasets. The average incremental percentages, calculated by the performance improvements over the baseline performance, were 97.8% in Intersection over Union (IoU) and 94.1% in Dice Similarity Coefficient (DSC) when comparing model explanations and ground-truth lesion areas. We further visualized baseline and template-guided model explanations on radiographs to showcase the performance of our approach. CONCLUSIONS: In the context of pneumothorax diagnoses, we proposed a template-guided approach for improving model explanations. Our approach not only aligns model explanations more closely with clinical insights but also exhibits extensibility to other thoracic diseases. We anticipate that our template guidance will forge a novel approach to elucidating AI models by integrating clinical domain expertise.

COMPANION-002 A clinical trial of investigational drug CTX-009 plus paclitaxel vs paclitaxel in second line advanced BTC.

Treatment options for patients with biliary tract cancer are limited, and the prognosis is poor. CTX-009, a novel bispecific antibody targeting both DLL4 and VEGF-A, has demonstrated antitumor activity in patients with advanced cancers as both a monotherapy and in combination with chemotherapy. In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR). Described here is the design of and rationale for COMPANION-002, a randomized phase II/III study, which will evaluate the safety and efficacy of CTX-009 in combination with paclitaxel versus paclitaxel alone as second-line treatment for patients with advanced biliary tract cancer. The primary end point is ORR, and crossover is allowed.Clinical Trial Registration: NCT05506943 (ClinicalTrials.gov).

Looking for new options for patients with advanced biliary tract cancer? Explore COMPANION-002, Compass Therapeutics' phase II/III study of CTX-009 + paclitaxel as a second line treatment.#CMPX #biotech #healthcare #rarecancer.

Comparing the Use of 80% Trichloroacetic Acid and 50% Trichloroacetic Acid for the Treatment of Ice Pick Acne Scars.

BACKGROUND: Chemical reconstruction of skin scars (CROSS) using high concentration trichloroacetic acid (TCA) is a safe, effective, and low-cost treatment for ice pick acne scars. OBJECTIVE: To compare the efficacy and effectiveness of the CROSS technique using 50% TCA and 80% TCA for treating ice pick scars. MATERIALS AND METHODS: A nonrandomized, single-blinded, and self-controlled clinical trial was undertaken. Four CROSS sessions were conducted using 50% TCA on the left hemiface and 80% TCA on the right hemiface. The E' chelle d'Evaluation Clinique des Cicatrices d'Acne (ECCA) acne grading scale was used to assess the scars pretreatment and posttreatment. Complications were evaluated after each session. RESULTS: Thirty-one patients participated in our study. Significant differences were found between pretreatment and posttreatment ECCA scores (p < .0001) on both hemifaces. Scores were significantly lower on the side treated with 80% TCA; however, there was no statistical significance in mean ECCA score differences (pretreatment minus posttreatment) between the 2 treatment sides. The adverse events were more serious on the sides treated with 80% TCA. CONCLUSION: The CROSS method using TCA was well-tolerated and effective for treating ice pick acne scars. Less severe complications were associated with 50% TCA, whereas efficacy was the same as 80% TCA.

[Kids Lung Registry and Child-EU Project - Progress in Rare and Interstitial Lung Diseases in Childhood Through Collaboration]. / Kinderlungenregister (chILD-EU) ­ Zusammenarbeit führt zu Fortschritten bei den seltenen und interstitiellen Lungenerkrankungen.

BACKGROUND: Progress in rare and interstitial lung disease in childhood can most usefully be achieved through systematic, registry-based collection. QUESTION AND METHODS: What are the practicalities and benefits of participating in the pediatric lung registry/chILD-EU project? We report our clinical experiences. RESULTS: Pediatricians and pediatric pulmonologists identify children with rare lung diseases. These are reported to the Kid's Lung Register after parental consent. Clinical data, imaging, and blood are sent to the registry. Genetic analysis can be arranged if desired. With completeness of the data, a peer-review process by pediatric radiology, possibly lung pathology, clinical and possibly genetic experts takes place in an interdisciplinary conference. A working diagnosis is established and communicated to the responsible physician via the registry and, if necessary, further discussed in case-related discussions. Assistance in entering the data is provided by the registry. Follow-ups are performed annually, and all registered physicians are invited to regular, web-based case discussions. Significant questions are answered in scientific projects and jointly published (>110 publications to date). CONCLUSIONS: Due to voluntary additional work of all participants beyond clinical routine, more than 1000 children with rare lung diseases have been included in the registry with biobank to date. A deeper understanding of the clinical courses of large cohorts of rare diseases and the initial description of new entities contributes to better care for these children.

WITHDRAWN: Neoadjuvant therapy leads to objective response in intrahepatic cholangiocarcinoma.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.hpb.2024.04.011. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

Neoadjuvant therapy leads to objective response in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is the second most common hepatic malignancy and has a poor prognosis. Surgical resection is the standard of care for patients with resectable disease, representing 30-40% of cases. Increasingly, neoadjuvant systemic therapy is being utilized in patients due to high-risk anatomic or biologic considerations. However, data on the clinical effect of this approach are limited. We performed a cohort study to evaluate the effect of neoadjuvant therapy in patients with oncologically high-risk iCCA. METHODS: iCCA patients (n = 181) between the years 2014-2020 were reviewed for clinical, histopathologic, treatment, and outcome-related data. Tumor regression grade was scored per CAP criteria for gastrointestinal carcinomas. RESULTS: 47 iCCA patients received neoadjuvant therapy and 72 did not. Neoadjuvant treatment led to objective response and tumor regression by CAP score. After adjustment for age, clinical stage, and tumor size, the outcomes of patients who had neoadjuvant therapy followed by surgery were not significantly different from those patients who had surgery first. DISCUSSION: In conclusion, neoadjuvant therapy in iCCA facilitated surgical care. The progression-free and overall survival for surgical patients with and without neoadjuvant therapy were not significantly different suggesting this approach needs further exploration as an effective treatment paradigm.

Tungsten-based nanocatalysts with different structures for visible light responsive photocatalytic degradation of bisphenol A.

Environmental pollution, such as water contamination, is a critical issue that must be absolutely addressed. Here, three different morphologies of tungsten-based photocatalysts (WO3 nanorods, WO3/WS2 nanobricks, WO3/WS2 nanorods) are made using a simple hydrothermal method by changing the solvents (H2O, DMF, aqueous HCl solution). The as-prepared nanocatalysts have excellent thermal stability, large porosity, and high hydrophilicity. The results show all materials have good photocatalytic activity in aqueous media, with WO3/WS2 nanorods (NRs) having the best activity in the photodegradation of bisphenol A (BPA) under visible-light irradiation. This may originate from increased migration of charge carriers and effective prevention of electron‒hole recombination in WO3/WS2 NRs, whereby this photocatalyst is able to generate more reactive •OH and •O2- species, leading to greater photocatalytic activity. About 99.6% of BPA is photodegraded within 60 min when using 1.5 g/L WO3/WS2 NRs and 5.0 mg/L BPA at pH 7.0. Additionally, the optimal conditions (pH, catalyst dosage, initial BPA concentration) for WO3/WS2 NRs are also elaborately investigated. These rod-like heterostructures are expressed as potential catalysts with excellent photostability, efficient reusability, and highly active effectivity in different types of water. In particular, the removal efficiency of BPA by WO3/WS2 NRs reduces by only 1.5% after five recycling runs and even reaches 89.1% in contaminated lake water. This study provides promising insights for the nearly complete removal of BPA from wastewater or different water resources, which is advantageous to various applications in environmental remediation.

Extracellular vesicles as natural therapeutic agents and innate drug delivery systems for cancer treatment: Recent advances, current obstacles, and challenges for clinical translation.

As cancer poses a significant threat to the well-being of humans on a global scale, many researchers have embarked on the search for effective anticancer therapeutic agents. In recent years, many drugs have been shown to have extraordinary anticancer effects. However, in a lot of cases the treatment is accompanied by undesirable side effects due to some intrinsic properties linked to the therapeutic agents, such as poor targeting selectivity and short half-life in the circulation. In this regard, extracellular vesicles (EVs), a diverse family of natural cell-derived vesicles, steal the show as potential anticancer immunotherapy or delivery vectors of anticancer agents since they are an innate mechanism of intercellular communication. Here, we describe some of the most hotly-debated issues regarding the use of EVs as anticancer therapeutics. First, we review the biology of EVs providing the most up-to-date definition of EVs as well as highlighting their circulation kinetics and homing properties. Next, we share our views on popular methods reported for EV isolation, characterization, and functional analysis. Pioneering and innovative reports along with emerging challenges in the field of EV imaging and EV drug loading strategies are then discussed. Finally, we examine in detail the therapeutic application of EVs in cancer treatment, including their role in cancer immunotherapy and as natural delivery systems for anticancer agents including natural compounds such as paclitaxel and doxorubicin. We consider standardised protocols and proper analytical approaches to be crucial in improving the reproducibility and rigor in EV research and ensuring the successful translation of EVs as anticancer therapeutics.

Spatiotemporal Evolution of SARS-CoV-2 Alpha and Delta Variants during Large Nationwide Outbreak of COVID-19, Vietnam, 2021.

We analyzed 1,303 SARS-CoV-2 whole-genome sequences from Vietnam, and found the Alpha and Delta variants were responsible for a large nationwide outbreak of COVID-19 in 2021. The Delta variant was confined to the AY.57 lineage and caused >1.7 million infections and >32,000 deaths. Viral transmission was strongly affected by nonpharmaceutical interventions.

The kinetochore module Okp1CENP-Q/Ame1CENP-U is a reader for N-terminal modifications on the centromeric histone Cse4CENP-A.

Kinetochores are supramolecular assemblies that link centromeres to microtubules for sister chromatid segregation in mitosis. For this, the inner kinetochore CCAN/Ctf19 complex binds to centromeric chromatin containing the histone variant CENP-A, but whether the interaction of kinetochore components to centromeric nucleosomes is regulated by posttranslational modifications is unknown. Here, we investigated how methylation of arginine 37 (R37Me) and acetylation of lysine 49 (K49Ac) on the CENP-A homolog Cse4 from Saccharomyces cerevisiae regulate molecular interactions at the inner kinetochore. Importantly, we found that the Cse4 N-terminus binds with high affinity to the Ctf19 complex subassembly Okp1/Ame1 (CENP-Q/CENP-U in higher eukaryotes), and that this interaction is inhibited by R37Me and K49Ac modification on Cse4. In vivo defects in cse4-R37A were suppressed by mutations in OKP1 and AME1, and biochemical analysis of a mutant version of Okp1 showed increased affinity for Cse4. Altogether, our results demonstrate that the Okp1/Ame1 heterodimer is a reader module for posttranslational modifications on Cse4, thereby targeting the yeast CCAN complex to centromeric chromatin.

Pembrolizumab near the end of life in patients with metastatic pancreatic cancer: a multi-site consecutive series to examine survival and patient treatment burden.

BACKGROUND: Pembrolizumab confers minimal benefit to most patients with pancreas cancer. We explored survival and patient treatment burden (for example, death within 14 days of therapy) in a subgroup who had early access to pembrolizumab . METHODS: This multisite study examined consecutive pancreas cancer patients, who received pembrolizumab from 2004 through 2022. Median overall survival of > 4 months was to be deemed favorable. Patient treatment burden and medical record quotations are presented descriptively. RESULTS: Forty-one patients (median age 66 years; range 36, 84) are included. Fifteen (37%) had dMMR, MSI-H, TMB-H, or Lynch syndrome; and 23 (56%) received concurrent therapy. The median overall survival was 7.2 months (95% confidence interval (CI): 5.2, 12.7 months); 29 were deceased at the time of reporting. Patients with dMMR, MSI-H, TMB-H, or Lynch syndrome had a lower risk of death: hazard ratio (HR): 0.29 (95% CI: 0.12, 0.72); p = 0.008. Medical record phrases ("brilliant response") aligned with the above. One patient died within 14 days of therapy, and one was in an intensive care unit within 30 days of death. Fifteen patients enrolled in hospice; four of these died < 3 days later. CONCLUSIONS: These unexpectedly favorable findings underscore the need for healthcare providers-including palliative care providers-to knowledgeably guide patients about cancer therapy even near the end of life.