Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Targeting CXCR4/CXCL12 axis via [177Lu]Lu-DOTAGA.(SA.FAPi)2 with CXCR4 antagonist in triple-negative breast cancer.

PURPOSE: Radiopharmaceutical therapies targeting fibroblast activation protein (FAP) have shown promising efficacy against many tumor types. But radiopharmaceuticals alone in most cases are insufficient to completely eradicate tumor cells, which can partially be attributed to the protective interplay between tumor cells and cancer-associated fibroblasts (CAFs). The C-X-C chemokine receptor type 4/C-X-C motif chemokine 12 (CXCR4/CXCL12) interaction plays an important role in orchestrating tumor cells and CAFs. We hereby investigated the feasibility and efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2, a FAP-targeting radiopharmaceutical, in combination with AMD3100, a CXCR4 antagonist, in a preclinical murine model of triple-negative breast cancer (TNBC). METHODS: Public database was first interrogated to reveal the correlation between CAFs' scores and the prognosis of TNBC patients, as well as the expression levels of FAP and CXCR4 in normal tissues and tumors. In vitro therapeutic efficacy regarding cell proliferation, migration, and colony formation was assessed in BALB/3T3 fibroblasts and 4T1 murine breast cancer cells. In vivo therapeutic efficacy was longitudinally monitored using serial 18F-FDG, [18F]AlF-NOTA-FAPI-04, and [68Ga]Ga-DOTA-Pentixafor PET/CT scans and validated using tumor sections through immunohistochemical staining of Ki-67, α-SMA, CXCR4, and CXCL12. Intratumoral abundance of myeloid-derived suppressive cells (MDSCs) was analyzed using flow cytometry in accordance with the PET/CT schedules. Treatment toxicity was evaluated by examining major organs including heart, lung, liver, kidney, and spleen. RESULTS: CAFs' scores negatively correlated with the survival of TNBC patients (p < 0.05). The expression of CXCR4 and FAP was both significantly higher in tumors than in normal tissues. The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 significantly suppressed cell proliferation, migration, and colony formation in cell culture, and exhibited synergistic effects in 4T1 tumor models along with a decreased number of MDSCs. PET/CT imaging revealed lowest tumor accumulation of 18F-FDG and [18F]AlF-NOTA-FAPI-04 on day 13 and day 14 after treatment started, both of which gradually increased at later time points. A similar trend was observed in the IHC staining of Ki-67, α-SMA, and CXCL12. CONCLUSION: The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs.

Global burden of atrial fibrillation/atrial flutter and its attributable risk factors from 1990 to 2021.

BACKGROUND: To devise effective preventive measures, a profound understanding of the evolving patterns and trends in atrial fibrillation (AF) and atrial flutter (AFL) burdens is pivotal. Our study was designed to quantify the burden and delineate the risk factors associated with AF and AFL across 204 countries and territories spanning 1990 to 2021. MATERIALS AND METHODS: Data pertaining to AF and AFL were sourced from the Global Burden of Disease Study (GBD) 2021 study. The burden of AF/AFL was evaluated using metrics such as incidence, disability-adjusted life years (DALYs), deaths, and their corresponding age-standardized rates (ASRs), stratified by age, sex, socio-demographic index (SDI), and human development index (HDI). The estimated annual percentage change (EAPC) was employed to quantify changes in ASRs. Population attributable fractions (PAFs) were calculated to determine the proportional contributions of major risk factors to age-standardized AF/AFL deaths. RESULTS: This analysis encompassed the period from 1990 to 2021. Globally, in 2021, there were 4.48 million incident cases (95% uncertainty interval [UI]: 3.61 to 5.70), 8.36 million DALYs (95% UI: 6.97 to 10.13), and 0.34 million deaths (95% UI: 0.29 to 0.37) attributed to AF/AFL. The AF/AFL burden in 2021, as well as its trends from 1990 to 2021, displayed substantial variations based on gender, SDI quintiles, and geographical regions. High systolic blood pressure emerged as the leading contributor to age-standardized AF/AFL incidence, prevalence, death, and DALYs rate globally among all potential risk factors, followed closely by high body mass index. CONCLUSION: Our study underscores the enduring significance of AF/AFL as a prominent public health concern worldwide, marked by profound regional and national variations. Despite the substantial potential for prevention and management of AF/AFL, there is a pressing imperative to adopt more cost-effective strategies and interventions to target modifiable risk factors, particularly in areas where the burden of AF/AFL is high or escalating.

Use of suboptimal control arms in randomized clinical trials of investigational cancer drugs in China, 2016-2021: An observational study.

BACKGROUND: The use of suboptimal controls in randomized trials of new cancer drugs can produce potentially unreliable clinical efficacy results over the current standard of care and expose patients to substandard therapy. We aim to investigate the proportion of randomized trials of investigational cancer drugs that used a suboptimal control arm and the number of trial participants at risk of exposure to suboptimal treatments in China. The association between the use of a suboptimal control and concluding statistical significance on the primary endpoint was also examined. METHODS AND FINDINGS: This observational study included randomized controlled trials (RCTs) of cancer drugs that were authorized by specific Chinese institutional review boards between 2016 and 2021, supporting investigational new drug applications of these drugs in China. The proportion of trials that used a suboptimal control arm and the total number of trial participants at risk of exposure to suboptimal treatments were calculated. In a randomized trial for a specific condition, a comparator was deemed suboptimal if it was not recommended by clinical guidelines published in priori or if there existed a regimen with a higher level of recommendation for the indication. The final sample included 453 Phase II/III and Phase III randomized oncology trials. Overall, 60 trials (13.2%) adopted a suboptimal control arm. Among them, 58.3% (35/60) used comparators that were not recommended by a prior guideline for the indication. The cumulative number of trial participants at risk of exposure to suboptimal treatments totaled 18,610 by the end of 2021, contributing 15.1% to the total number of enrollees of all sampled RCTs in this study. After adjusting for the year of ethical approval, region of participant recruitment, line of therapy, and cancer site, second-line therapies (adjusted odds ratio [aOR] = 2.7, 95%CI [1.2, 5.9]), adjuvant therapies (aOR = 8.9, 95% CI [3.4, 23.1]), maintenance therapies (aOR = 5.2, 95% CI [1.6, 17.0]), and trials recruiting participants in China only (aOR = 4.1, 95% CI [2.1, 8.0]) were more likely to adopt a suboptimal control. For the 105 trials with publicly available results, no statistically significant difference was observed between the use of a suboptimal control and concluding positive on the primary endpoint (100.0% [12/12] versus 83.9% [78/93], p = 0.208). The main limitation of this study is its reliance on clinical guidelines that could vary across cancer types and time in assessing the quality of the control groups. CONCLUSIONS: In this study, over one-eighth of randomized trials of cancer drugs registered to apply for regulatory approval in China used a suboptimal comparator. Our results highlight the necessity to refine the design of randomized trials to generate optimal clinical evidence for new cancer therapies.

CTPC, a combined transcriptome data set of human prostate cancer cell lines.

BACKGROUND: Cell lines are the most used model system in cancer research. The transcriptomic data of established prostate cancer (PCa) cell lines help researchers explore differential gene expressions across the various PCa cell lines. METHODS: Through large scale datamining, we established a curated Combined Transcriptome dataset of PCa Cell lines (CTPC) which contains the transcriptomic data of 1840 samples of 9 commonly used PCa cell lines including LNCaP, LNCaP-95, LNCaP-abl, C4-2, VCaP, 22Rv1, PC3, DU145, and NCI-H660. RESULTS: The CTPC dataset provides an opportunity for researchers to not only compare gene expression across different PCa cell lines but also retrieve the experiment information and associate the differential gene expression data with meta data, such as gene manipulation and drug treatment information. Additionally, based on the CTPC dataset, we built a platform for users to visualize the data (https://pcatools.shinyapps.io/CTPC_V2/). CONCLUSIONS: It is our hope that the combined CTPC dataset and the user-friendly platform are of great service to the PCa research community.

The ubiquitin-binding protein MdRAD23D1 mediates drought response by regulating degradation of the proline-rich protein MdPRP6 in apple (Malus domestica).

RAD23 (RADIATION SENSITIVE23) proteins are a group of UBL-UBA (ubiquitin-like-ubiquitin-associated) proteins that shuttle ubiquitylated proteins to the 26S proteasome for breakdown. Drought stress is a major environmental constraint that limits plant growth and production, but whether RAD23 proteins are involved in this process is unclear. Here, we demonstrated that a shuttle protein, MdRAD23D1, mediated drought response in apple plants (Malus domestica). MdRAD23D1 levels increased under drought stress, and its suppression resulted in decreased stress tolerance in apple plants. Through in vitro and in vivo assays, we demonstrated that MdRAD23D1 interacted with a proline-rich protein MdPRP6, resulting in the degradation of MdPRP6 by the 26S proteasome. And MdRAD23D1 accelerated the degradation of MdPRP6 under drought stress. Suppression of MdPRP6 resulted in enhanced drought tolerance in apple plants, mainly because the free proline accumulation is changed. And the free proline is also involved in MdRAD23D1-mediated drought response. Taken together, these findings demonstrated that MdRAD23D1 and MdPRP6 oppositely regulated drought response. MdRAD23D1 levels increased under drought, accelerating the degradation of MdPRP6. MdPRP6 negatively regulated drought response, probably by regulating proline accumulation. Thus, "MdRAD23D1-MdPRP6" conferred drought stress tolerance in apple plants.

LITTLELEAF (LL) encodes a WD40 repeat domain-containing protein associated with organ size variation in cucumber.

Plants employ tight genetic control to integrate intrinsic growth signals and environmental cues to enable organs to grow to a defined size. Many genes contributing to cell proliferation and/or cell expansion, and consequently organ size control, have been identified, but the regulatory pathways are poorly understood. Here we have characterized a cucumber littleleaf (ll) mutant which exhibits smaller organ sizes but more lateral branches than the wild type. The small organ size in ll was due to a reduction of both cell number and cell size. Quantitative trait locus (QTL) analyses revealed co-localization of major-effect QTLs for fruit size, fruit and seed weight, as well as number of lateral branches, with the LL locus indicating pleiotropic effects of the ll mutation. We demonstrate that LL is an ortholog of Arabidopsis STERILE APETALA (SAP) encoding a WD40 repeat domain-containing protein; the mutant protein differed from the wild type by a single amino acid substitution (W264G) in the second WD40 repeat. W264 was conserved in 34 vascular plant genomes examined. Phylogenetic analysis suggested that LL originated before the emergence of flowering plants but was lost in the grass genome lineage. The function of LL in organ size control was confirmed by its overexpression in transgenic cucumbers and ectopic expression in Arabidopsis. Transcriptome profiling in LL and ll bulks revealed a complex regulatory network for LL-mediated organ size variation that involves several known organ size regulators and associated pathways. The data support LL as an important player in organ size control and lateral branch development in cucumber.

PET imaging of EGFR expression using an 18F-labeled RNA aptamer.

OBJECTIVE: Epidermal growth factor receptor (EGFR) is a theranostic biomarker for a variety of cancer types. The aim of the present study was to develop an 18F radiolabeled EGFR targeting RNA aptamer, and to investigate its ability to visualize and quantify EGFR in xenograft models. METHODS: Biolayer interferometry binding assay was used to detect the binding affinity of the alkyne-modified EGFR aptamer MinE07 (denoted as ME07) with recombinant human wild-type EGFR protein and the mutant EGFRvIII protein. Cy5-conjugated ME07 was used for flow cytometry and immunofluorescence staining, and an Alexa Fluor 488-labeled EGFR antibody (ab193244) was used as a control. 18F-Fluorobenzoyl (FB) azide was employed as a synthon to produce 18F-FB-ME07 via click chemistry, and the cellular uptake and internalization characteristics of 18F-FB-ME07 were investigated. Static PET scans, 60-min dynamic scans, and biodistribution study of 18F-FB-ME07 were performed in three types of tumor models. RESULTS: The Kd values of ME07 to wtEGFR and EGFRvIII proteins were 0.3 nM and 271 nM respectively. The A431, U87MG, and HCT-116 cells showed strong, weak, and negative binding with Cy5-ME07, which is consistent with EGFR expression level in these cells. Peak cell uptake values of 18F-FB-ME07 in A431, U87MG and HCT-116 cells were 2.86%, 2.19% and 0.88% of the added dose respectively. The mean internalization of 18F-FB-ME07 in these cells were 60.02%, 53.1%, and 52.8% of the total accumulated radioactivity. In static PET imaging, despite high uptake in the liver and kidneys, 18F-FB-ME07 showed reasonable accumulation in A431 tumors (1.02 ± 0.13 %ID/g at 30 min after injection). Of note, the uptake of 18F-FB-ME07 in A431 xenografts was significantly higher than that in U87MG and HCT-116 xenografts. In A431 xenografted mice, the tumor/blood ratio was 3.89 and the tumor/muscle ratio reached 8.65. CONCLUSIONS: We for the first time generated an aptamer-derived EGFR targeting PET tracer 18F-FB-ME07, which showed highly selective targeting ability in mouse tumor models expressing different levels of EGFR. Our results suggest that 18F-FB-ME07 is a potential EGFR targeting molecular imaging probe for future clinical translation.

Monitoring the Response of PD-L1 Expression to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Nonsmall-Cell Lung Cancer Xenografts by Immuno-PET Imaging.

Accumulating evidence has suggested that the tumor microenvironment of nonsmall-cell lung cancer (NSCLC) may be impacted by chemotherapy, radiotherapy, or epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). PD-L1 is an important biomarker in the tumor microenvironment that can predict patient response to immunotherapies. Therefore, it is highly desirable to achieve a real-time, noninvasive assessment of PD-L1 expression, which can provide critical information for recruiting patients as well as monitoring therapeutic efficacy. We herein studied the EGFR-TKI-induced effects on PD-L1 levels in NSCLC tumor models using immuno-PET imaging with 89Zr-Df-KN035, an imaging tracer previously established by our group. A549 human NSCLC xenografts were established in BALB/c nude mice and treated with different doses of an EGFR-TKI gefitinib. PET imaging with 89Zr-Df-KN035 was performed before and after the treatment to evaluate PD-L1 expression, which was further verified by immunohistochemical staining. Our results demonstrate that 89Zr-Df-KN035 can specifically evaluate PD-L1 levels in NSCLC tumor models. Compared to the untreated control, the high dose of gefitinib inhibited tumor growth and lowered the tumor uptake of 89Zr-Df-KN035. In comparison, the low dose of gefitinib did not affect tumor growth, although the extensive tumor necrosis also led to the lower uptake of 89Zr-Df-KN035. In conclusion, our results demonstrate that immuno-PET imaging with 89Zr-Df-KN035 is a promising tool to noninvasively monitor PD-L1 expression in NSCLC treated with EGFR-TKIs and can be used to optimize treatment plans for immunotherapy.

Wnt/Beta-Catenin Signaling and Prostate Cancer Therapy Resistance.

Metastatic or locally advanced prostate cancer (PCa) is typically treated with androgen deprivation therapy (ADT). Initially, PCa responds to the treatment and regresses. However, PCa almost always develops resistance to androgen deprivation and progresses to castrate-resistant prostate cancer (CRPCa), a currently incurable form of PCa. Wnt/ß-Catenin signaling is frequently activated in late stage PCa and contributes to the development of therapy resistance. Although activating mutations in the Wnt/ß-Catenin pathway are not common in primary PCa, this signaling cascade can be activated through other mechanisms in late stage PCa, including cross talk with other signaling pathways, growth factors and cytokines produced by the damaged tumor microenvironment, release of the co-activator ß-Catenin from sequestration after inhibition of androgen receptor (AR) signaling, altered expression of Wnt ligands and factors that modulate the Wnt signaling, and therapy-induced cellular senescence. Research from genetically engineered mouse models indicates that activation of Wnt/ß-Catenin signaling in the prostate is oncogenic, enables castrate-resistant PCa growth, induces an epithelial-to-mesenchymal transition (EMT), promotes neuroendocrine (NE) differentiation, and confers stem cell-like features to PCa cells. These important roles of Wnt/ß-Catenin signaling in PCa progression underscore the need for the development of drugs targeting this pathway to treat therapy-resistant PCa.

A sRNA in a reduced mutualistic symbiont genome regulates its own gene expression.

Similar to other nutritional endosymbionts that are obligate for host survival, the mutualistic aphid endosymbiont, Buchnera, has a highly reduced genome with few regulatory elements. Until recently, it was thought that aphid hosts were primarily responsible for regulating their symbiotic relationship. However, we recently revealed that Buchnera displays differential protein regulation, but not mRNA expression. We also identified a number of conserved small RNAs (sRNAs) that are expressed among Buchnera taxa. In this study, we investigate whether differential protein regulation in Buchnera is the result of post-transcriptional gene regulation via sRNAs. We characterize the sRNA profile of two Buchnera life stages: (i) when Buchnera is transitioning from an extracellular proliferating state in aphid embryos and (ii) when Buchnera is in an intracellular nonproliferating state in aphid bacteriocytes (specialized symbiont cells). Overall, we identified 90 differentially expressed sRNAs, 97% of which were upregulated in aphid embryos. Of these sRNAs, the majority were predicted to be involved in the regulation of various metabolic processes, including arginine biosynthesis. Using a heterologous dual expression vector, we reveal for the first time that a Buchnera antisense sRNA can post-transcriptionally interact with its cognate Buchnera coding sequence, carB, a gene involved in arginine biosynthesis. These results corroborate our in vivo RNAseq and proteomic data, where the candidate antisense sRNA carB and the protein CarB are significantly upregulated in aphid embryos. Overall, we demonstrate that Buchnera may regulate gene expression independently from its host by utilizing sRNAs.

Positron Emission Tomography Imaging of Prostate Cancer with Ga-68-Labeled Gastrin-Releasing Peptide Receptor Agonist BBN7-14 and Antagonist RM26.

Radiolabeled bombesin (BBN) analogs have long been used for developing gastrin-releasing peptide receptor (GRPR) targeted imaging probes, and tracers with excellent in vivo performance including high tumor uptake, high contrast, and favorable pharmacokinetics are highly desired. In this study, we compared the 68Ga-labeled GRPR agonist (Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2, BBN7-14) and antagonist (d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) for the positron emission tomography (PET) imaging of prostate cancer. The in vitro stabilities, receptor binding, cell uptake, internalization, and efflux properties of the probes 68Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-Aca-BBN7-14 and 68Ga-NOTA-poly(ethylene glycol)3 (PEG3)-RM26 were studied in PC-3 cells, and the in vivo GRPR targeting abilities and kinetics were investigated using PC-3 tumor xenografted mice. BBN7-14, PEG3-RM26, NOTA-Aca-BBN7-14, and NOTA-PEG3-RM26 showed similar binding affinity to GRPR. In PC-3 tumor-bearing mice, the tumor uptake of 68Ga-NOTA-PEG3-RM26 remained at around 3.00 percentage of injected dose per gram of tissue within 1 h after injection, in contrast with 68Ga-NOTA-Aca-BBN7-14, which demonstrated rapid elimination and high background signal. Additionally, the majority of the 68Ga-NOTA-PEG3-RM26 remained intact in mouse serum at 5 min after injection, while almost all of the 68Ga-NOTA-Aca-BBN7-14 was degraded under the same conditions, demonstrating more-favorable in vivo pharmacokinetic properties and metabolic stabilities of the antagonist probe relative to its agonist counterpart. Overall, the antagonistic GRPR targeted probe 68Ga-NOTA-PEG3-RM26 is a more-promising candidate than the agonist 68Ga-NOTA-Aca-BBN7-14 for the PET imaging of prostate cancer patients.

Correction to: PET imaging of EGFR expression using an 18F-labeled RNA aptamer.

The original version of this article contained a mistake in the first paragraph of "Cell uptake and internalization of 18F-FB-ME07" section. The text "The specific activity was 7.4-14.8 kBq/nmol" should have been "The specific activity was 7.4-14.8 Mbq/nmol".

Immuno-PET Imaging of 89Zr Labeled Anti-PD-L1 Domain Antibody.

Recently, various immuno-PET tracers based on monoclonal antibodies (mAbs), engineered scaffold proteins, and peptides were developed to target either programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1), showing promise in assessment of immune checkpoints. We sought to develop an immunotherapeutic agent based PET probe that enables real-time assessment of PD-L1 expression and evaluation of antibody drug biodistribution to select eligible candidates for anti-PD-1/PD-L1 immunotherapies. KN035, a 79.6 kDa size anti-PD-L1 domain antibody under analysis in clinical trials, was used to develop the immuno-PET probe, 89Zr-Df-KN035. Immuno-PET studies were performed to monitor PD-L1 levels in nude mice bearing LN229 xenografts with positive expression for PD-L1, and to evaluate the whole-body biodistribution in healthy non-human primates (NHPs). LN229 xenografts were markedly visualized from 24 h after injection of 89Zr-Df-KN035, with elevated accumulation persisting for up to 120 h. Tumor radioactivity was notably reduced in the presence of excess KN035. Mouse ex vivo biodistribution studies performed at 24 and 120 h revealed tumor-to-muscle ratios as high as 5.64 ± 0.65 and 7.70 ± 1.37, respectively. In the NHP model, PET imaging demonstrated low background. The liver and kidney showed moderate accumulation with the highest SUVmean value of 1.15 ± 0.15 and 2.13 ± 0.10 at 72 h, respectively. The spleen, lymph nodes, and salivary glands were also slightly visualized. In conclusion, 89Zr-Df-KN035, a novel anti-PD-L1 domain antibody-based probe, shows the feasibility of noninvasive in vivo evaluation of PD-L1 expression. This work further provides a template for immunotherapeutic agent based imaging to evaluate human PD-L1 expression and to augment our understanding of therapeutic agent biodistribution, leading to better therapeutic strategies in the future.

Polymeric Nanoparticles with a Glutathione-Sensitive Heterodimeric Multifunctional Prodrug for In Vivo Drug Monitoring and Synergistic Cancer Therapy.

Polymeric micelle-based drug delivery systems have dramatically improved the delivery of small molecular drugs, yet multiple challenges remain to be overcome. A polymeric nanomedicine has now been engineered that possesses an ultrahigh loading (59 %) of a glutathione (GSH)-sensitive heterodimeric multifunctional prodrug (HDMP) to effectively co-deliver two synergistic drugs to tumors. An HDMP comprising of chemotherapeutic camptothecin (CPT) and photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-α (HPPH) was conjugated via a GSH-cleavable linkage. The intrinsic fluorogenicity and label-free radio-chelation (64 Cu) of HPPH enabled direct drug monitoring by fluorescence imaging and positron emission tomography (PET). Through quantitative PET imaging, HDMP significantly improves drug delivery to tumors. The high synergistic therapeutic efficacy of HDMP-loaded NPs highlights the rational design of HDMP, and presents exciting opportunities for polymer NP-based drug delivery.

Rooting for cassava: insights into photosynthesis and associated physiology as a route to improve yield potential.

Contents 50 I. 50 II. 52 III. 54 IV. 55 V. 57 VI. 57 VII. 59 60 References 61 SUMMARY: As a consequence of an increase in world population, food demand is expected to grow by up to 110% in the next 30-35 yr. The population of sub-Saharan Africa is projected to increase by > 120%. In this region, cassava (Manihot esculenta) is the second most important source of calories and contributes c. 30% of the daily calorie requirements per person. Despite its importance, the average yield of cassava in Africa has not increased significantly since 1961. An evaluation of modern cultivars of cassava showed that the interception efficiency (ɛi ) of photosynthetically active radiation (PAR) and the efficiency of conversion of that intercepted PAR (ɛc ) are major opportunities for genetic improvement of the yield potential. This review examines what is known of the physiological processes underlying productivity in cassava and seeks to provide some strategies and directions toward yield improvement through genetic alterations to physiology to increase ɛi and ɛc . Possible physiological limitations, as well as environmental constraints, are discussed.

Dynamic Fluid in a Porous Transducer-Based Angular Accelerometer.

This paper presents a theoretical model of the dynamics of liquid flow in an angular accelerometer comprising a porous transducer in a circular tube of liquid. Wave speed and dynamic permeability of the transducer are considered to describe the relation between angular acceleration and the differential pressure on the transducer. The permeability and streaming potential coupling coefficient of the transducer are determined in the experiments, and special prototypes are utilized to validate the theoretical model in both the frequency and time domains. The model is applied to analyze the influence of structural parameters on the frequency response and the transient response of the fluidic system. It is shown that the radius of the circular tube and the wave speed affect the low frequency gain, as well as the bandwidth of the sensor. The hydrodynamic resistance of the transducer and the cross-section radius of the circular tube can be used to control the transient performance. The proposed model provides the basic techniques to achieve the optimization of the angular accelerometer together with the methodology to control the wave speed and the hydrodynamic resistance of the transducer.

Investigation of the Association Between e-Cigarette Smoking and Oral Mucosal Health Status Among Young People: Protocol for a Case-Control Trial.

BACKGROUND: Given the paucity of current safety studies related to e-cigarettes, there are no definitive studies on whether e-cigarettes cause oral mucosal lesions or even oral cancer. Although it is still undetermined whether e-cigarettes are harmless, an increasing number of teenagers choose to smoke e-cigarettes and believe that they are not harmful to the human body. OBJECTIVE: This aims to determine whether e-cigarettes cause damage to the oral mucosa. This study also aims to evaluate the association between e-cigarette smoking and oral mucous membrane lesions in young adults. The objectives are to (1) compare the oral mucosal conditions in participants with and without e-cigarette smoking habits, (2) assess the effect of the amount of e-cigarette smoking on oral mucosal conditions, and (3) assess the effect of the duration of e-cigarette smoking on oral mucosal conditions. METHODS: In this prospective study, 304 youths aged 15 to 24 years (n=152, 50% who smoke only e-cigarettes and n=152, 50% who do not smoke e-cigarettes or cigarettes) will be divided into 2 groups for a controlled study. Whether e-cigarettes cause oral mucosal lesions will be verified by comparing the odds of oral mucosal lesions in the 2 experimental groups. For this experiment, the predefined power is 80% (P=.04), and the predefined proportions of groups 1 and 2 are 11% and 2.5%, respectively. RESULTS: This experiment is at the conceptualization phase and has not yet been carried out. Experimenters have not been recruited and no data have been collected. CONCLUSIONS: e-Cigarettes are still an unfamiliar topic to the public, and it is still unknown whether they can cause damage to the oral mucosa. This experiment aims to find out whether there is a link between the 2. There are still many limitations in this study, such as the lack of categorization of e-cigarettes and the lack of testing methods for oral mucosal status. These limitations are expected to be addressed in the future as the experiment is formally conducted and further optimized. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/53644.

PCTA, A PAN-CANCER CELL LINE TRANSCRIPTOME ATLAS.

Background: A substantial volume of RNA sequencing data were generated from cancer cell lines. However, it requires specific bioinformatics skills to compare gene expression levels across cell lines. This has hindered non-bioinformaticians from fully utilizing these valuable datasets in their research. To bridge this gap, we established a curated Pan-cancer Cell Line Transcriptome Atlas (PCTA) dataset. This resource aims to provide a user-friendly platform, allowing researchers without extensive bioinformatics expertise to access and leverage the wealth of information within the dataset for their studies. Importantly, PCTA stands out by offering sufficient sample numbers per cell line in comparison to other pan-cancer datasets. Methods: Cell lines' meta data and RNA sequencing data were retrieved from the Cancer Cell Line Encyclopedia (CCLE), SRA and ARCHS4 databases. Utilizing the programming language R, we conducted data retrieval, normalization, and visualization. Only expression data for protein-coding genes and long-non-coding RNAs (LncRNAs) were considered in this study, streamlining the focus to enhance the precision and relevance of the analysis. Results: The resulting PCTA dataset encompasses the expression matrix of 24,965 genes, featuring data from 84,385 samples derived from 5,677 studies. This comprehensive compilation spans 535 cell lines, representing a spectrum of 114 cancer types originating from 30 diverse tissue types. On UMAP plots, cell lines originating from the same type of tissue tend to cluster together, illustrating the dataset's ability to capture biological relationships. To unravel molecular signatures, marker genes were identified for each cancer type. Additionally, an interactive and user-friendly web application (https://pcatools.shinyapps.io/PCTA_app/ ) was developed for researchers to explore the PCTA dataset. This platform allows users to examine the expression pattern of their genes of interest across a diverse array of samples. Data are visualized as violin-, box-, and point- plots, enhancing the interpretability of the findings. Conclusion: The PCTA stands as a comprehensive resource, offering insights into gene expression patterns across diverse cancer cell lines and providing a valuable tool to explore molecular signatures and potential therapeutic targets in cancer research.

PCTA, a pan-cancer cell line transcriptome atlas.

A substantial volume of RNA sequencing data have been generated from cancer cell lines. However, it requires specific bioinformatics skills to compare gene expression levels across cell lines. This has hindered non-bioinformaticians from fully utilizing these valuable datasets in their research. To bridge this gap, we established a curated Pan-cancer Cell Line Transcriptome Atlas (PCTA) dataset. This resource aims to provide a user-friendly platform, allowing researchers without extensive bioinformatics expertise to access and leverage the wealth of information within the dataset for their studies. The PCTA dataset encompasses the expression matrix of 24,965 genes, featuring data from 84,385 samples derived from 5677 studies. This comprehensive compilation spans 535 cell lines, representing a spectrum of 114 cancer types originating from 30 diverse tissue types. On UMAP plots, cell lines originating from the same type of tissue tend to cluster together, illustrating the dataset's ability to capture biological relationships. Additionally, an interactive and user-friendly web application (https://pcatools.shinyapps.io/PCTA_app/) was developed for researchers to explore the PCTA dataset. This platform allows users to examine the expression of their genes of interest across a diverse array of samples.