Some Multiplicity Adjustment Procedures for Clinical Trials with Sequential Design and Multiple Endpoints

This article proposes some new multiplicity adjustment procedures for clinical trials with multiple endpoints and multiple interim analyses. The proposed sequential procedures, adapting the popular multiple comparison procedures for fixed time-point design and using α-spending for each endpoint, are shown to strongly control the family-wise Type-1 error rate and provide powerful yet versatile multiplicity adjustment solutions for monitoring multiple endpoints via interim analyses.</p

Strategy for combining information from Real World Data Sources When Individual Patient Data Are Not Simultaneously Accessible

Some research on the population in a European country, referred to as the target population, may not provide a sufficient sample size and require pooling multiple national data sources. The researcher can access multiple national data sources one at a time but cannot access them simultaneously at an individual patient level, because of regulation requirements on data sharing. We propose a strategy that enables the combination of information from multiple data sources when IPD are not simultaneously accessible to researchers. This strategy starts with a protocol for extracting information consistently from all data sources. It utilizes the matching adjusted indirect comparison (MAIC) approach to derive the weights to align the means of the identified covariates of each data source to those of a target study population. The final analysis will be a meta-analysis on the weight adjusted estimates of treatment effect from individual data sources.</p

R_codes – Supplemental material for Design and monitoring of survival trials based on restricted mean survival times

Supplemental material, R_codes for Design and monitoring of survival trials based on restricted mean survival times by Xiaodong Luo, Bo Huang and Hui Quan in Clinical Trials</p

Eliminating Ferroelectric Hysteresis in All-Two-Dimensional Gate-Stack Negative-Capacitance Transistors

Boltzmann distribution thermal tails of carriers restrain the subthreshold swing (SS) of field-effect transistors (FETs) to be lower than 60 mV/decade at room temperature, which restrains the reduction of operate-voltage and power consumption of transistors. The negative-capacitance FET (NC FET) is expected to break through this physical limit and obtain a steep SS by amplifying the gate voltage through the negative capacitance effect of the ferroelectric thin film, providing a new way to further reduce the power consumption of the transistor at the end of Moore’s law. Here, we show a MoS2 NC FET with a CuInP2S6 ferroelectric, exhibiting a large on/off ratio of 108, a steep SS as low as 6 mV/decade, and a wide sub-60 mV/decade drain current range of more than 4 orders of magnitude while sacrificially inducing a huge hysteresis larger than 500 mV. Furthermore, we found that by inserting the h-phase boron nitride (h-BN) layer with suitable thickness, the dielectric capacitance matches the ferroelectric negative capacitance better, and thus the hysteresis on the transfer curve is reduced, and the ideal switching-behavior transistors with SS as low as 62 mV/decade and only 5 mV negligible hysteresis were obtained. Our work demonstrates that under the capacitance–matching condition, the hysteresis-free negative-capacitance transistors do not act as the predicted steep-slope transistors, but their voltage-saving still occurs instead as a type of effective transconductance booster with more than 20 times transconductance amplification

A Case Study of 2-Stage Seamless Adaptive Sample Size Re-Estimation Design with Efficacy Interim Analysis When Slope Is the Primary Endpoint

Due to highly unmet medical needs in rare disease areas, there is great desire to speed up the drug development process. A two-stage adaptive design option for a placebo-controlled registration study is being evaluated. Stage 1 consists of participants in an ongoing phase 2 study with 1-year double blinded (DB) treatment and Stage 2 includes newly enrolled participants with 2-year DB treatment period. The primary endpoint is the annualized rate of change (slope) for a continuous longitudinal measurement, which will be evaluated through a random coefficient linear mixed model. An unblinded interim analysis will be performed using Stage 1 data to re-estimate the sample size for Stage 2, followed by another interim analysis for potential early efficacy stopping when all participants completed the 1-year DB treatment. To control the overall Type 1 error rate, rather than using a conservative approach, the actual correlation between the interim and final test statistics will be taken into account to determine the final significance level given the pre-specified significance level for the interim efficacy analysis. Multiplicity adjustments for secondary endpoints including considerations for order switching between interim and final analysis in this specific case study will also be discussed.</p

Side Chain Programming Synchronously Enhances the Photothermal Conversion Efficiency and Photodynamic Activity of A–D–A Photosensitizers

Synchronously improving the photothermal conversion efficiency and photodynamic activity of organic small molecule photosensitizers is crucial for their further wide application in cancer treatment. Recently, the emerging A–D–A photosensitizer-based phototherapy systems have attracted great interest due to their plentiful inherent merits. Herein, we propose a design strategy for A–D–A photosensitizers with synchronously enhanced photothermal conversion and reactive oxygen species (ROS) generation efficiencies. Side chain programming is carried out to design three A–D–A photosensitizers (IDT-H, IDT-Br, IDT-I) containing hexyl, bromohexyl, and iodohexyl side chains, respectively. Theoretical calculations confirm that a bulky iodine atom could weaken the intermolecular π–π stacking and enhance spin–orbit coupling constants of IDT-I. These molecular mechanisms enable IDT-I nanoparticles (NPs) to exhibit 2.4-fold and 1.7-fold higher ROS generation efficiency than that of IDT-H NPs and IDT-Br NPs, respectively, as well as the highest photothermal conversion efficiency. Both the experimental results in vitro and in vivo verify that IDT-I NPs are perfectly qualified for the mission of photothermal and photodynamic synergistic therapy. Therefore, in this contribution, we provide a promising perspective for the design of A–D–A photosensitizers with simultaneously improved photothermal and photodynamic therapy ability

Structural Flexibility and Conformation Features of Cyclic Dinucleotides in Aqueous Solutions

Cyclic dinucleotides are able to trigger the innate immune system by activating STING. It was found that the binding affinity of asymmetric 2′3′-cGAMP to symmetric dimer of STING is 3 orders of magnitude higher than that of the symmetric 3′3′-cyclic dinucleotides. Such a phenomenon has not been understood yet. Here we show that the subtle changes in phosphodiester linkage of CDNs lead to their distinct structural properties which correspond to the varied binding affinities. 2′–5′ and/or 3′–5′ linked CDNs adopt specific while different types of ribose puckers and backbone conformations. That ribose conformations and base types have different propensities for <i>anti</i> or <i>syn</i> glycosidic conformations further affects the overall flexibility of CDNs. The counterbalance between backbone ring tension and electrostatic repulsion, both affected by the ring size, also contributes to the different flexibility of CDNs. Our calculations reveal that the free energy cost for 2′3′-cGAMP to adopt the STING-bound structure is smaller than that for 3′3′-cGAMP and cyclic-di-GMP. These findings may serve as a reference for design of CDN-analogues as vaccine adjuvants. Moreover, the cyclization pattern of CDNs closely related to their physiological roles suggests the importance of understanding structural properties in the study of protein–ligand interactions

Mitochondria-Targeting Multimodal Phototheranostics Based on Triphenylphosphonium Cation Modified Amphiphilic Pillararenes and A–D–A Fused-Ring Photosensitizers

Tumor-targeting phototheranostics has gradually developed as a powerful tool for the precise diagnosis and treatment of cancer. However, the designs of tumor-targeting phototheranostics agents with excellent multimodal phototherapy and fluorescence imaging (FLI) capability, as well as very few components, are still scarce and challenging for cancer treatment. Herein, a mitochondria-targeting multimodal phototheranostics system has been constructed by combining a designed amphiphilic pillararene WP5–2PEG–2TPP and the A–D–A fused-ring photosensitizer F8CA5. WP5–2PEG–2TPP is constructed by attaching the triphenylphosphonium cations to our previously reported dual PEG-functionalized amphiphilic pillararene, which can self-assemble into regular spherical nanocarriers with outstanding mitochondria targeting and water solubility. The A–D–A photosensitizer F8CA5 containing two methyl cyanoacetate group modified end groups displays superior photothermal conversion ability and dual type I/II photodynamic activity as well as strong NIR fluorescence emission. Through their strong union, multifunctional mitochondria-targeting phototheranostics agent F8CA5 NPs were obtained to be applied into FLI-guided synergistic photothermal and type I/II photodynamic therapy. As a result, F8CA5 NPs show good mitochondria-targeting and phototherapy effects in various tumor cells. Not only that, they can combat tumor hypoxia, which hinders the efficacy of photodynamic therapy. Therefore, this work provides a creative ideal for the construction of multifunctional tumor-targeting phototheranostic agents with excellent performance

Effects of AICAR on the removal of apoptotic cells <i>in vivo</i>.

<p>Mice were injected intraperitoneally with AICAR (0 or 500 mg/kg) 4 h before intratracheal administration of apoptotic neutrophils or thymocytes. <b>(A)</b> Bronchoalveolar (BAL) fluids were collected 2 h after administration of apoptotic neutrophils. Cytospin slides were prepared from BAL fluid and stained with HEMA3, and the phagocytosis index was determined as described in the Materials and Methods. <b>(B)</b> BAL fluids were collected 90 min after administration of PKH26-labelled apoptotic thymocytes. Samples were stained with FITC-conjugated CD11b antibody and APC-conjugated CD 90.2 antibody. The phagocytic index was calculated as described in the Materials and Methods. (C) BAL fluids were collected 4 h after administration of apoptotic thymocytes and the IL-10 levels in the BAL fluids were determined using an enzyme-linked immunosorbent assay. Values represent the mean ± SD from five mice per group. *<i>P</i> < 0.05 compared with the control group.</p

Inhibition of p38 MAPK activity suppresses AICAR-induced efferocytosis.

<p><b>(A)</b> RAW 264.7 cells were cultured with AICAR at the indicated doses for 1 h and then incubated with apoptotic thymocytes for 90 min followed by flow cytometry. Each bar represents the mean ± SD (n = 4). <b>(B)</b> RAW 264.7 cells were cultured with AICAR (2 mM) for the indicated times. Cell lysates were subjected to Western blot analysis using specific antibodies. <b>(C)</b> Representative Western blots show the levels of p38α or actin in RAW 264.7 cells treated with control siRNA or siRNA specific to p38α. <b>(D)</b> RAW 264.7 cells treated with control siRNA or siRNA specific to p38α were incubated with AICAR (0 or 2 mM) for 1 h and then cultured with apoptotic thymocytes for an additional 90 min, followed by flow cytometry. *<i>P</i> < 0.05 compared with the control. ^†<i>P</i> < 0.05 compared with control cells treated with AICAR. Each bar represents the mean ± SD (n = 4). <b>(E)</b> Peritoneal macrophages cultured with AICAR (0.3 mM) for the indicated times and subjected to Western blot analysis. <b>(F, G)</b> Macrophages were cultured with LY294002, a PI3K inhibitor, at the indicated concentrations for 30 min before exposure to AICAR (0 or 0.3 mM) for 1 h, followed by <b>(F)</b> Western blot analysis or <b>(G)</b> culturing with apoptotic thymocytes for an additional 90 min. The phagocytic indexes were measured by flow cytometry. Values represent the mean ± SD from four independent experiments. *<i>P</i> < 0.05 compared with untreated cells.</p