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Supplementary Methods, Figure Legends 1-8 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo

Supplementary Figure 3b from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo

PDF file - 648K, Figure S1. TAS-117 is a novel potent and selective inhibitor of Akt kinases. Figure S2. Basal expression of phosphorylated Akt and Akt in MM cell lines. Figure S3. TAS-117 inhibits neither MEK/ERK nor JAK2/STAT pathway. Figure S4. TAS-117 modulates phenotype of side population (SP) cells and induces cytotoxicity in SP cells associated with Akt inhibition. Figure S5. TAS-117 overcomes cytoprotective effects conferred by cytokines by blocking Akt activation. Figure S6. TAS-117 treatment does not affect viability in BMSCs. Figure S7. TAS-117 triggers cleavage of caspase and PARP in MM cells. Figure S8. TAS-117 induces autophagosome formation in MM cells. Figure S9. TAS-117 in combination with bortezomib does not affect body weight of mice. Figure S10. TAS-117 in combination with carfilzomib induces synergistic cytotoxicity in RPMI8226 cells with low baseline of p-Akt, associated with inhibition of carfilzomib-induced p-Akt. Table S1. TAS-117 combination indices (CI) with bortezomib in MM.1S cells. Table S2. TAS-117 combination indices (CI) with bortezomib in RPMI8226 cells. Table S3. TAS-117 combination indices (CI) with carfilzomib in MM.1S cells. Table S4. TAS-117 combination indices (CI) with carfilzomib in RPMI8226 cells.

Supplementary Figure 8 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo

Supplementary Figure 4 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo

Supplementary Table 1 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo

Background/objectivesDifferent genetic variants are associated with larger body size in childhood vs adulthood. Whether and when these variants predominantly influence adiposity are unknown. We examined how genetic variants influence total body fat and total lean mass trajectories.MethodsData were from the Avon Longitudinal Study of Parents and Children birth cohort (N = 6926). Sex-specific genetic risk scores (GRS) for childhood and adulthood body size were generated, and dual-energy X-ray absorptiometry scans measured body fat and lean mass six times between the ages of 9 and 25 years. Multilevel linear spline models examined associations of GRS with fat and lean mass trajectories.ResultsIn males, the sex-specific childhood and adulthood GRS were associated with similar differences in fat mass from 9 to 18 years; 8.3% [95% confidence interval (CI) 5.1, 11.6] and 7.5% (95% CI 4.3, 10.8) higher fat mass at 18 years per standard deviation (SD) higher childhood and adulthood GRS, respectively. In males, the sex-combined childhood GRS had stronger effects at ages 9 to 15 than the sex-combined adulthood GRS. In females, associations for the sex-specific childhood GRS were almost 2-fold stronger than the adulthood GRS from 9 to 18 years: 10.5% (95% CI 8.5, 12.4) higher fat mass at 9 years per SD higher childhood GRS compared with 5.1% (95% CI 3.2, 6.9) per-SD higher adulthood GRS. In females, the sex-combined GRS had similar effects, with slightly larger effect estimates. Lean mass effect sizes were much smaller.ConclusionsGenetic variants for body size are more strongly associated with adiposity than with lean mass. Sex-combined childhood variants are more strongly associated with increased adiposity until early adulthood. This may inform future studies that use genetics to investigate the causes and impact of adiposity at different life stages.

Purpose This study aims to propose an approach towards reducing differences between national economies and living standards existing between the world’s wealthiest and least affluent nations. Design/methodology/approach A systemic review identifies the impeding purpose as proposed above: an entirely new initiative. Findings The efforts recommended are vital for preserving the human species and ensuring the integrity of our planet. For both the future of the human species and the planet itself, it is essential to reduce the divide between wealthy and poor. Now is the time to give force to the types of implementation necessary to meet these combined goals. Research limitations/implications This essay avoids dissecting problems of current geopolitical and ideological character. Despite their sometimes contentious nature, they are often reduced by intelligent diplomacy. Originality/value The study proposes a holistic approach to bridging the North-South divide.

Determining how high body-mass index (BMI) at different time points influences the risk of developing type two diabetes (T2D), and affects insulin secretion and insulin sensitivity, is critical. By estimating childhood BMI in 441,761 individuals in the UK Biobank, we identified which genetic variants had larger effects on adulthood BMI than on childhood BMI, and vice-versa. All genome-wide significant genetic variants were then used to separate the independent genetic effects of high childhood BMI from high adulthood BMI on the risk of T2D and insulin related phenotypes using Mendelian randomisation and studies of T2D, and oral and intravenous measures of insulin secretion and sensitivity. We found that a 1.s.d. (= 1.97kg/m2) higher childhood BMI, corrected for the independent genetic liability to adulthood BMI, was associated with a protective effect for seven measures of insulin sensitivity and secretion, including an increased insulin sensitivity index (β = 0.15 [0.067, 0.225], p = 2.79×10−4), and reduced fasting glucose (β = -0.053 [-0.089, -0.017], p = 4.31×10−3). There was however little to no evidence of a direct protective effect on T2D (OR = 0.94 [0.85 - 1.04], p = 0.228), independently of genetic liability to adulthood BMI. Our results thus cumulatively provide evidence of the protective effect of higher childhood BMI on insulin secretion and sensitivity, which are crucial intermediate diabetes traits. However, we stress that our results should not currently lead to any change in public health or clinical practice, given the uncertainty in biological pathway of these effects, and the limitations of this type of study.Research in ContextHigh BMI in adulthood is associated with higher risk of type two diabetes, coupled with lower insulin sensitivity and secretion.Richardson et al [2020] used genetics to show that high BMI in childhood does not appear to increase the risk of type diabetes independently from its effect on adult BMI.We asked: does high childhood BMI affect insulin related traits such as fasting glucose and insulin sensitivity, independently of adulthood BMI?We used genetics to show that high childhood BMI has a protective effect on seven insulin sensitivity and secretion traits, including fasting glucose and measures of insulin sensitivity and secretion, independently of adulthood BMI.Our work has the potential to turn conventional understanding on its head – high BMI in childhood improves insulin sensitivity (when adjusting for knock on effects to high adult BMI) and opens up important questions about plasticity in childhood and compensatory mechanisms.

Key Points Defibrotide is associated with encouraging responses in the real world, including VOD/SOS after MAC as well as RIC allogeneic HSCT.Early diagnosis, prompt initiation of defibrotide, and minimization of dosing interruptions may be key to successful treatment of VOD/SOS., Visual Abstract, Hepatic veno-occlusive disease or sinusoidal obstructive syndrome (VOD/SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Defibrotide is the only medication approved by the US Food and Drug Administration for the management of severe VOD/SOS after HSCT. We report our center’s experience with commercially available defibrotide as treatment of patients with VOD/SOS. We retrospectively identified 28 cases of VOD/SOS, based on the European Society for Blood and Marrow Transplantation criteria, from March 2016 through June 2019. The median day of VOD/SOS onset was 25 days (range, 8-69 days), and defibrotide was initiated on day of diagnosis in 71% of patients. Complete resolution of VOD/SOS occurred in 75% of patients. Day 100 survival was 64% for all HSCT patients and 53% for those with very severe VOD/SOS. Response rates and survival were similar in patients with VOD/SOS after myeloablative or reduced-intensity chemotherapy HSCT. Therapy-related adverse events were mild and included hematuria (43%), epistaxis (18%), and hypotension (11%). Severe hemorrhagic adverse events occurred in 2 patients (pulmonary hemorrhage and upper gastrointestinal hemorrhage; 7%) and both in the setting of progressive VOD/SOS. Early diagnosis, prompt initiation of defibrotide, and minimization of dosing interruptions may be key to successful treatment of VOD/SOS.

Developing functional insight into the causal molecular drivers of immunological disease is a critical challenge in genomic medicine. Here, we systematically apply Mendelian randomization (MR), genetic colocalization, immune-cell-type enrichment, and phenome-wide association methods to investigate the effects of genetically predicted gene expression on ten immune-associated diseases and four cancer outcomes. Using whole blood-derived estimates for regulatory variants from the eQTLGen consortium (n = 31,684), we constructed genetic risk scores for 10,104 genes. Applying the inverse-variance-weighted MR method transcriptome wide while accounting for linkage disequilibrium structure identified 664 unique genes with evidence of a genetically predicted effect on at least one disease outcome (p < 4.81 × 10(−5)). We next undertook genetic colocalization to investigate cell-type-specific effects at these loci by using gene expression data derived from 18 types of immune cells. This highlighted many cell-type-dependent effects, such as PRKCQ expression and asthma risk (posterior probability = 0.998), which was T cell specific. Phenome-wide analyses on 311 complex traits and endpoints allowed us to explore shared genetic architecture and prioritize key drivers of disease risk, such as CASP10, which provided evidence of an effect on seven cancer-related outcomes. Our atlas of results can be used to characterize known and novel loci in immune-associated disease and cancer susceptibility, both in terms of elucidating cell-type-dependent effects as well as dissecting shared disease pathways and pervasive pleiotropy. As an exemplar, we have highlighted several key findings in this study, although similar evaluations can be conducted via our interactive web platform.

Purpose:Although remarkably effective in some patients, precision medicine typically induces only transient responses despite initial absence of resistance-conferring mutations. Using BRAF-mutated myeloma as a model for resistance to precision medicine we investigated if BRAF-mutated cancer cells have the ability to ensure their survival by rapidly adapting to BRAF inhibitor treatment.Experimental Design:Full-length single-cell RNA (scRNA) sequencing (scRNA-seq) was conducted on 3 patients with BRAF-mutated myeloma and 1 healthy donor. We sequenced 1,495 cells before, after 1 week, and at clinical relapse to BRAF/MEK inhibitor treatment. We developed an in vitro model of dabrafenib resistance using genetically homogeneous single-cell clones from two cell lines with established BRAF mutations (U266, DP6). Transcriptional and epigenetic adaptation in resistant cells were defined by RNA-seq and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq). Mitochondrial metabolism was characterized by metabolic flux analysis.Results:Profiling by scRNA-seq revealed rapid cellular state changes in response to BRAF/MEK inhibition in patients with myeloma and cell lines. Transcriptional adaptation preceded detectable outgrowth of genetically discernible drug-resistant clones and was associated with widespread enhancer remodeling. As a dominant vulnerability, dependency on oxidative phosphorylation (OxPhos) was induced. In treated individuals, OxPhos was activated at the time of relapse and showed inverse correlation to MAPK activation. Metabolic flux analysis confirmed OxPhos as a preferential energetic resource of drug-persistent myeloma cells.Conclusions:This study demonstrates that cancer cells have the ability to rapidly adapt to precision treatments through transcriptional state changes, epigenetic adaptation, and metabolic rewiring, thus facilitating the development of refractory disease while simultaneously exposing novel vulnerabilities.

In the Phase III ICARIA-MM study (NCT02990338), the addition of the anti-CD38 monoclonal antibody isatuximab to pomalidomide and dexamethasone led to increased progression-free survival and improved response rates in patients with relapsed/refractory multiple myeloma. There is an unmet treatment need, particularly among patients with poor prognoses, including those with high-risk cytogenetics, those who have renal impairment, those who are elderly and those who are refractory to prior lines of treatment. In this review, the subgroup analyses from the ICARIA-MM study, representing subpopulations with poor prognostic factors, are discussed. Overall, the addition of isatuximab to pomalidomide and dexamethasone improved progression-free survival and disease response rates across different subgroups, regardless of prognostic factor.Lay abstract Currently, the majority of patients with multiple myeloma are not cured, and current treatments may not be helpful for patients with poor prognoses, including those with high-risk chromosomal changes, those who have impaired kidney function, those who are elderly and those who are refractory to prior treatments. In this review, we will discuss the benefits of the combination of isatuximab plus pomalidomide and dexamethasone in these difficult-to-treat patients.

Relapsed and refractory multiple myeloma (RRMM) presents a therapeutic challenge due to the development of drug resistance. Panobinostat is an oral histone deacetylase inhibitor (HDACi) that affects multiple cellular pathways and has demonstrated the ability to resensitize refractory-multiple myeloma cells in preclinical studies, as well as in patients with RRMM in clinical trials. Synergy of panobinostat with a number of different classes of antimyeloma drugs (proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies) has also been shown. Panobinostat is a promising HDACi for the treatment of multiple myeloma. Here, we present a comprehensive review of preclinical and clinical studies of panobinostat.

Background Chimeric antigen receptor (CAR) T cells have achieved remarkable responses in patients with hematological malignancies; however, the potential of this therapeutic platform for solid tumors like glioblastoma (GBM) has been limited, due in large part to the targeting of single antigens in a heterogeneous disease. Strategies that allow CAR T cells to engage multiple antigens concomitantly may broaden therapeutic responses and mitigate the effects of immune escape. Methods Here we have developed a novel, dual-specific, tandem CAR T (TanCART) cell with the ability to simultaneously target both EGFRvIII and IL-13Rα2, two well-characterized tumor antigens that are frequently found on the surface of GBM cells but completely absent from normal brain tissues. We employed both standard immunological assays and multiple orthotopic preclinical models including patient-derived xenograft to demonstrate efficacy of this approach against heterogeneous tumors. Results Tandem CAR T cells displayed enhanced cytotoxicity in vitro against heterogeneous GBM populations, including patient-derived brain tumor cultures (P < .05). Compared to CAR T cells targeting single antigens, dual antigen engagement through the tandem construct was necessary to achieve long-term, complete, and durable responses in orthotopic murine models of heterogeneous GBM, including patient-derived xenografts (P < .05). Conclusions We demonstrate that TanCART is effective against heterogeneous tumors in the brain. These data lend further credence to the development of multi-specific CAR T cells in the treatment of GBM and other cancers.

High-dose melphalan (HDM) improves progression-free survival in multiple myeloma (MM), yet melphalan is a DNA-damaging alkylating agent; therefore, we assessed its mutational effect on surviving myeloma cells by analyzing paired MM samples collected at diagnosis and relapse in the IFM 2009 study. We performed deep whole-genome sequencing on samples from 68 patients, 43 of whom were treated with RVD (lenalidomide, bortezomib, and dexamethasone) and 25 with RVD + HDM. Although the number of mutations was similar at diagnosis in both groups (7137 vs 7230; P = .67), the HDM group had significantly more mutations at relapse (9242 vs 13 383, P = .005). No change in the frequency of copy number alterations or structural variants was observed. The newly acquired mutations were typically associated with DNA damage and double-stranded breaks and were predominantly on the transcribed strand. A machine learning model, using this unique pattern, predicted patients who would receive HDM with high sensitivity, specificity, and positive prediction value. Clonal evolution analysis showed that all patients treated with HDM had clonal selection, whereas a static progression was observed with RVD. A significantly higher percentage of mutations were subclonal in the HDM cohort. Intriguingly, patients treated with HDM who achieved complete remission (CR) had significantly more mutations at relapse yet had similar survival rates as those treated with RVD who achieved CR. This similarity could have been due to HDM relapse samples having significantly more neoantigens. Overall, our study identifies increased genomic changes associated with HDM and provides rationale to further understand clonal complexity.

Liquid xenon time projection chambers are promising detectors to search for neutrinoless double beta decay (0$$\nu \beta \beta $$ ν β β ), due to their response uniformity, monolithic sensitive volume, scalability to large target masses, and suitability for extremely low background operations. The nEXO collaboration has designed a tonne-scale time projection chamber that aims to search for 0$$\nu \beta \beta $$ ν β β of $$^{136}$$ 136 Xe with projected half-life sensitivity of $$1.35\times 10^{28}$$ 1.35 × 10 28 yr. To reach this sensitivity, the design goal for nEXO is $$\le $$ ≤ 1% energy resolution at the decay Q-value ($$2458.07\pm 0.31$$ 2458.07 ± 0.31 keV). Reaching this resolution requires the efficient collection of both the ionization and scintillation produced in the detector. The nEXO design employs Silicon Photo-Multipliers (SiPMs) to detect the vacuum ultra-violet, 175 nm scintillation light of liquid xenon. This paper reports on the characterization of the newest vacuum ultra-violet sensitive Fondazione Bruno Kessler VUVHD3 SiPMs specifically designed for nEXO, as well as new measurements on new test samples of previously characterised Hamamatsu VUV4 Multi Pixel Photon Counters (MPPCs). Various SiPM and MPPC parameters, such as dark noise, gain, direct crosstalk, correlated avalanches and photon detection efficiency were measured as a function of the applied over voltage and wavelength at liquid xenon temperature (163 K). The results from this study are used to provide updated estimates of the achievable energy resolution at the decay Q-value for the nEXO design.

BackgroundFindings from Mendelian randomization (MR) studies are conventionally interpreted as lifelong effects, which typically do not provide insight into the molecular mechanisms underlying the effect of an exposure on an outcome. In this study, we apply two recently developed MR approaches (known as ‘lifecourse’ and ‘tissue-partitioned’ MR) to investigate lifestage specific effects and tissues of action in the relationship between adiposity and circulating leptin levels.MethodGenetic instruments for childhood and adult adiposity were used to estimate lifestage specific effects on leptin levels measured during early life (mean age:10 years) in the Avon Longitudinal Study of Parents and Children (ALSPAC) and in adulthood (mean age:55 years) using summary-level data from the deCODE Health study. This was followed by partitioning body mass index (BMI) instruments into those whose effects are putatively mediated by gene expression in either subcutaneous adipose or brain tissues, followed by using MR to simultaneously estimate their separate effects on childhood and adult leptin levels.ResultsThere was strong evidence that childhood adiposity has a direct effect on leptin levels at age 10 years in the lifecourse (Beta=1.10, 95% CI=0.90 to 1.30, P=6×10−28), whereas evidence of an indirect effect was found on adulthood leptin along the causal pathway involving adulthood body size (Beta=0.74, 95% CI=0.62 to 0.86, P=1×10−33). Tissue-partitioned MR analyses provided evidence to suggest that BMI exerts its effect on leptin levels during both childhood and adulthood via brain-tissue mediated pathways (Beta=0.79, 95% CI=0.22 to 1.36, P=6×10−3& Beta=0.51, 95% CI=0.32 to 0.69, P=1×10−7respectively).ConclusionsOur findings demonstrate the use of lifecourse MR to disentangle direct and indirect effects of early life exposures on time-varying complex outcomes. Furthermore, by integrating tissue-specific data, we highlight the aetiological importance of appetite regulation in the effect of adiposity on leptin levels, as well as raising implications for the gene-environment equivalence assumption in MR.FundingThis work was supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1).

Background Body mass index (BMI) is known to influence the risk of various site-specific cancers, however, dissecting which subcomponents of this heterogenous risk factor are predominantly responsible for driving disease effects has proven difficult to establish. We have leveraged tissue-specific gene expression to separate the effects of distinct phenotypes underlying BMI on the risk of seven site-specific cancers. Methods SNP-exposure estimates were weighted in a multivariable Mendelian randomisation analysis by their evidence for colocalization with subcutaneous adipose- and brain-tissue-derived gene expression using a recently developed methodology. Results Our results provide evidence that brain-tissue-derived BMI variants are predominantly responsible for driving the genetically predicted effect of BMI on lung cancer (OR: 1.17; 95% CI: 1.01–1.36; P = 0.03). Similar findings were identified when analysing cigarettes per day as an outcome (Beta = 0.44; 95% CI: 0.26–0.61; P = 1.62 × 10−6), highlighting a possible shared aetiology or mediator effect between brain-tissue BMI, smoking and lung cancer. Our results additionally suggest that adipose-tissue-derived BMI variants may predominantly drive the effect of BMI and increased risk for endometrial cancer (OR: 1.71; 95% CI: 1.07–2.74; P = 0.02), highlighting a putatively important role in the aetiology of endometrial cancer. Conclusions The study provides valuable insight into the divergent underlying pathways between BMI and the risk of site-specific cancers.

Background: Iberdomide is a novel cereblon E3 ligase modulator with enhanced tumouricidal and immune-stimulatory effects compared with immunomodulatory drugs. In preclinical myeloma models, iberdomide has shown synergy with dexamethasone, proteasome inhibitors, and CD38 monoclonal antibodies. We aimed to evaluate the safety and clinical activity of iberdomide plus dexamethasone in patients with heavily pretreated relapsed or refractory multiple myeloma. Methods: We conducted a multicohort, open-label, phase 1/2 trial (CC-220-MM-001) at 42 treatment centres in Europe, Canada, and the USA. Patients aged 18 years or older with multiple myeloma who had received at least two previous lines of therapy, including lenalidomide or pomalidomide and a proteasome inhibitor, were enrolled into the dose-escalation cohort. Patients received escalating doses of oral iberdomide (0·3–1·6 mg on days 1–21 of each 28-day cycle) plus oral dexamethasone (40 mg [20 mg if age >75 years] once per week). A dose-expansion cohort at the recommended phase 2 dose was planned for patients who had received at least three previous lines of therapy and had triple-class refractory disease (refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies). Treatment continued until progressive disease or unacceptable toxicity. The primary outcomes were the recommended phase 2 dose (in the dose-escalation cohort, phase 1) and overall response rate (defined as complete response or partial response; in the dose-expansion cohort, phase 2) in the full analysis set. This trial is ongoing and is registered with ClinicalTrials.gov, NCT02773030. Findings: Between Dec 5, 2016, and Dec 16, 2020, 460 patients were assessed for eligibility across all cohorts and 197 were enrolled and treated with iberdomide plus dexamethasone (90 patients in the dose-escalation cohort and 107 in the dose-expansion cohort). In the dose-escalation cohort, 47 (52%) patients were female and 43 (48%) were male, 70 (78%) were White, and the median number of previous lines of therapy was 5 (IQR 4–8). In the dose-expansion cohort, 47 (44%) were female and 60 (56%) were male, 84 (79%) were White, and the median number of previous lines of therapy was 6 (IQR 5–8). At data cutoff (June 2, 2021), median follow-up was 5·8 months (IQR 3·0–13·7) in the dose-escalation cohort and 7·7 months (5·3–11·4) in the dose-expansion cohort. Two dose-limiting toxicities (both infections, at 1·2 mg and 1·3 mg) were observed in the dose-escalation cohort, and 1·6 mg was selected as the recommended phase 2 dose. In the dose-escalation cohort, the overall response rate was 32% (95% CI 23–43; 29 of 90 patients) across all doses, and the maximum tolerated dose was not reached. In the dose-expansion cohort, the overall response rate was 26% (95% CI 18–36; 28 of 107 patients). The most common grade 3 or worse adverse events were neutropenia (48 [45%] of 107 patients), anaemia (30 [28%]), infection (29 [27%]), and thrombocytopenia (23 [22%]). Serious adverse events occurred in 57 (53%) patients. There was one (1%) treatment-related death (sepsis) and five (5%) patients discontinued iberdomide due to adverse events. Interpretation: Iberdomide plus dexamethasone was generally safe and showed meaningful clinical activity in heavily pretreated patients with multiple myeloma, including in disease that was refractory to immunomodulatory drugs. These data suggest that further evaluation of iberdomide plus dexamethasone or other standard antimyeloma therapies is warranted. Funding: Bristol Myers Squibb.

Physics-based electrochemical battery models derived from porous electrode theory are a very powerful tool for understanding lithium-ion batteries, as well as for improving their design and management. Different model fidelity, and thus model complexity, is needed for different applications. For example, in battery design we can afford longer computational times and the use of powerful computers, while for real-time battery control (e.g. in electric vehicles) we need to perform very fast calculations using simple devices. For this reason, simplified models that retain most of the features at a lower computational cost are widely used. Even though in the literature we often find these simplified models posed independently, leading to inconsistencies between models, they can actually be derived from more complicated models using a unified and systematic framework. In this review, we showcase this reductive framework, starting from a high-fidelity microscale model and reducing it all the way down to the Single Particle Model (SPM), deriving in the process other common models, such as the Doyle-Fuller-Newman (DFN) model. We also provide a critical discussion on the advantages and shortcomings of each of the models, which can aid model selection for a particular application. Finally, we provide an overview of possible extensions to the models, with a special focus on thermal models. Any of these extensions could be incorporated into the microscale model and the reductive framework re-applied to lead to a new generation of simplified, multi-physics models., 50 pages, 9 figures

Background Immune ageing is a phenomenon which includes lymphopenia, expansion of pro-inflammatory T-lymphocyte subsets and telomere shortening. While lymphopenia predicts mortality after myocardial infarction (MI), MI itself leads to both an increase in terminally differentiated memory CD8+ T-lymphocytes (CD8+ TEMRAs) and a decrease in telomere length. Activation of telomerase has been shown to ameliorate lymphopenia, and improve heart function after MI in mouse models. TA-65 is an oral telomerase activator, which may ameliorate immune ageing and improve outcome after MI. Methods This double-blinded, randomized placebo-controlled pilot study evaluated the use of TA-65 in 90 MI patients over 65 years, the average onset age for immune ageing. Patients were randomised to either TA-65 (16 mg daily, n=45) or placebo (n=45) for 12 months. The majority of patients underwent percutaneous coronary intervention (87%) or coronary artery bypass surgery (2%) as treatment for their index MI. The pre-defined primary endpoint was the proportion of CD8+ TEMRA T-lymphocytes at 12 months, a marker of immune ageing. A linear mixed effects model was used for the analysis. Results The proportion of CD8+ TEMRAs after 12 months did not differ between the 2 treatment groups, although only increased significantly in the placebo group (+2.2%, 95% CI: 0.14–4.24). TA-65 was well tolerated, with total adverse events lower in the treatment group (TA-65 vs. placebo group: n=130 vs. n=185). We observed at 12 months a 62% reduction in mean high-sensitivity CRP (hsCRP: TA-65 vs. placebo group: 1.1±0.9 vs. 2.9±6.4 mg/L) and a 15%-increase in mean peripheral blood lymphocytes in TA-65 after 12 months. In the whole sample, among those who were treated with TA-65 compared to Placebo, after 12 months peripheral blood lymphocytes increased (+285 cells /μl, 95% CI: 117–452). The latter was due to significant increases in the TA-65 group from baseline to 12 months across all major lymphocyte populations: CD3+ (+15%), CD4+ (+14%),CD8+ T-lymphocytes (+19%), B-lymphocytes (+17%) and natural killer cells (+12%), while no changes occurred in major lymphocyte populations in the placebo group over the course of the study. Conclusion In this randomised clinical trial, we found that while CD8+ TEMRAs were not significantly altered after 12 months, the telomerase activator TA-65 significantly increased all major lymphocyte subsets and substantially reduced hsCRP at 12 months in patients with MI. These findings suggest TA-65 holds great promise in potentially reducing inflammation while improving an age-related decline in major lymphocyte populations, thereby enhancing immunity. A larger, multicentre, powered phase IIb efficacy trial to examine the potential effect of TA-65 in prognosis and heart function after MI is therefore warranted. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): TA-Science, New York, USA

Spontaneous neural activity has become increasingly linked to behavioral and cognitive output. A specific cognitive control mode, proactive control, uses prior information to plan and prepare the brain to be particularly sensitive to incoming goal-directed stimuli. Little is known about specific proactive mechanisms implemented via preparatory patterns of spontaneous neural activity, that may enable dynamically enhanced cognitive performance. In this study, humans implanted with intracranial electrodes performed a simple cognitive task. For each subject, pre-trial spectral power and communicability-based features from both grey and white matter nodes were extracted to identify preparatory control states that were “primed to perform”. The anatomical structure and topology of these states across subjects demonstrated a critical role for white matter communicability in decoding and intrinsically controlling preparatory network activity. Our results provide novel insights for putative cognitive network control and may be studied to develop prosthetic approaches for individuals with cognitive deficits.

Background: eMental health apps are increasingly being considered for use in health care with growing recognition of the importance of considering end-user preferences in their design and implementation. The key to the success of using apps with Indigenous youth is tailoring the design and content to include Indigenous perspectives. In this study we used a Two-Eyed Seeing perspective to integrate Indigenous and human computer interaction methodologies to identify end-user preferences for a tablet-based mental health screening app used in a primary care clinic serving Indigenous youth. Objective: The research objectives used a Two-Eyed Seeing approach to (i) collectively create stories about Indigenous youth lived experiences accessing integrated primary care for their mental health concerns; and (ii) engage Indigenous youth in Design Circles to determine their usability preferences for digital mental health screening tools. Method: Eight adolescents (n = 4 young women; n = 3 young men; and n = 1 Two Spirit) between 20 to 24 years old who self-identified as Indigenous participated. Indigenous youth joined Design Circles to co-create a story about accessing mental health care and their needs and preferences for an eMental Health app. Results: Findings highlighted the importance of collective Indigenous storytelling about accessing integrated primary care for mental health needs. Participants created three persona stories about their challenges accessing mental health care and the role of social support. Participants sorted their usability design preferences for an eMental Health app to be inclusive of Indigenous knowledges. Conclusions: A Two-Eyed Seeing perspective was useful to incorporate a design thinking approach as collective storytelling among Indigenous youth. This research may inform and shape the design of eMental health apps used in health clinics to better engage Indigenous youth.

Aim Rate of surgical site infections (SSI) in orthopaedic surgery is low but can have disastrous consequences. The aim of this study was to assess the impact of Covid-19 measures on the rate of SSI and subsequent readmissions in orthopaedic patients. Method Retrospective, observational study comparing rates of SSI in orthopaedic patients who underwent surgery prior to the Covid-19 lockdown versus that of patients who underwent surgery during the lockdown period. A total of 1151 patients were identified using electronic clinical records over two different time periods: 3 months pre Covid-19 lockdown (n=680) and 3 months during the Covid-19 lockdown (n=470). Patients were followed up for 1 year following their initial procedure. Primary outcome was readmission for SSI. Results The most commonly performed procedures were arthroplasty and manipulation under anaesthesia with 119 in lockdown vs 101 non-lockdown (p=0.001). The readmission rate was higher in the lockdown group with 61 (13%) vs 44 (6.5%) in the non-lockdown group (p Conclusion Whilst Covid-19 precautions were associated with higher readmission rates, there was no significant difference in rate of SSI between the two groups.

PURPOSE In the phase II ELOQUENT-3 trial (ClinicalTrials.gov identifier: NCT02654132 ), elotuzumab combined with pomalidomide/dexamethasone (EPd) significantly improved progression-free survival (PFS) versus pomalidomide/dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM) previously treated with lenalidomide and a proteasome inhibitor (PI). Here, we present the final overall survival (OS) results. METHODS Patients with RRMM who had received ≥ 2 prior lines of therapy, with disease refractory to last therapy and either refractory or relapsed and refractory to lenalidomide and a PI were randomly assigned (1:1) to receive EPd or Pd. The primary end point was PFS per investigator assessment. ORR and OS were secondary end points planned to be tested hierarchically. RESULTS A total of 117 patients were randomly assigned to EPd (n = 60) and Pd (n = 57). Among treated patients (EPd 60, Pd 55), there were 37 (61.7%) deaths in the EPd group and 41 (74.5%) in the Pd group, most commonly because of disease progression (EPd 41.7%, Pd 49.1%). Median (95% CI) OS was significantly improved with EPd (29.8 [22.9 to 45.7] months) versus Pd (17.4 [13.8 to 27.7] months), with a hazard ratio of 0.59 (95% CI, 0.37 to 0.93; P = .0217). OS benefit with EPd was observed in most patient subgroups. The safety profile of EPd was consistent with prior reports with no new safety signals detected. CONCLUSION EPd demonstrated a statistically significant improvement in OS versus Pd in patients with RRMM previously treated with lenalidomide and a PI who had disease refractory to last therapy. In this setting, ELOQUENT-3 is the first randomized study of a triplet regimen incorporating a monoclonal antibody and Pd to improve both PFS and OS significantly.

Funder: National Institute for Health Research (NIHR), Funder: Wellcome Trust, Funder: Medical Research Council, BACKGROUND: Interleukin 6 (IL-6) signaling is being investigated as a therapeutic target for atherosclerotic cardiovascular disease (CVD). While changes in circulating high-sensitivity C-reactive protein (hsCRP) are used as a marker of IL-6 signaling, it is not known whether there is effect heterogeneity in relation to baseline hsCRP levels or other cardiovascular risk factors. The aim of this study was to explore the association of genetically predicted IL-6 signaling with CVD risk across populations stratified by baseline hsCRP levels and cardiovascular risk factors. METHODS: Among 397,060 White British UK Biobank participants without known CVD at baseline, we calculated a genetic risk score for IL-6 receptor (IL-6R)-mediated signaling, composed of 26 variants at the IL6R gene locus. We then applied linear and non-linear Mendelian randomization analyses exploring associations with a combined endpoint of incident coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, and cardiovascular death stratifying by baseline hsCRP levels and cardiovascular risk factors. RESULTS: The study participants (median age 59 years, 53.9% females) were followed-up for a median of 8.8 years, over which time a total of 46,033 incident cardiovascular events occurred. Genetically predicted IL-6R-mediated signaling activity was associated with higher CVD risk (hazard ratio per 1-mg/dL increment in absolute hsCRP levels: 1.11, 95% CI: 1.06-1.17). The increase in CVD risk was linearly related to baseline absolute hsCRP levels. There was no evidence of heterogeneity in the association of genetically predicted IL-6R-mediated signaling with CVD risk when stratifying the population by sex, age, body mass index, estimated glomerular filtration rate, or systolic blood pressure, but there was evidence of greater associations in individuals with low-density lipoprotein cholesterol ≥ 160 mg/dL. CONCLUSIONS: Any benefit of inhibiting IL-6 signaling for CVD risk reduction is likely to be proportional to absolute reductions in hsCRP levels. Therapeutic inhibition of IL-6 signaling for CVD risk reduction should therefore prioritize those individuals with the highest baseline levels of hsCRP.

Introduction Multiple myeloma (MM) is an increasingly treatable but still incurable hematologic malignancy. Prognosis has improved significantly over recent years, although further advances remain urgently needed, especially for patients with heavily pre-treated and resistant disease for whom there are limited options. Selinexor is a first-in-class, oral, selective inhibitor of nuclear export (SINE) compound that triggers apoptosis in malignant cells by inducing nuclear retention of oncogene messenger RNAs (mRNAs) and reactivation of tumor suppressor proteins (TSPs). In clinical studies of patients with relapsed and/or refractory MM, selinexor has demonstrated both manageable toxicity and encouraging efficacy. Areas covered This review will provide an overview of the mechanism of action of selinexor as well as the efficacy and safety data from clinical studies using selinexor for the treatment of multiple myeloma. Expert opinion Long-term outcomes for patients with MM will continue to improve due to numerous recent and imminent therapeutic advances, although critical areas of unmet need remain. Oral selinexor is likely to contribute to the meeting of these needs and the further advancement of MM therapy in a meaningful way.

Immune profiling in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM) provides the framework for developing novel immunotherapeutic strategies. Here, we demonstrate decreased CD4+ Th cells, increased Treg and G-type MDSC, and upregulation of immune checkpoints on effector/regulatory and CD138+ cells in MM patients, compared MGUS/SMM patients or healthy individuals. Among the checkpoints profiled, LAG3 was most highly expressed on proliferating CD4+ Th and CD8+ Tc cells in MM patients BMMC and PBMC. Treatment with antibody targeting LAG3 significantly enhanced T cells proliferation and activities against MM. XBP1/CD138/CS1-specific CTL generated in vitro displayed anti-MM activity, which was further enhanced following anti-LAG3 treatment, within the antigen-specific memory T cells. Treg and G-type MDSC weakly express LAG3 and were minimally impacted by anti-LAG3. CD138+ MM cells express GAL-3, a ligand for LAG3, and anti-GAL-3 treatment increased MM-specific responses, as observed for anti-LAG3. Finally, we demonstrate checkpoint inhibitor treatment evokes non-targeted checkpoints as a cause of resistance and propose combination therapeutic strategies to overcome this resistance. These studies identify and validate blockade of LAG3/GAL-3, alone or in combination with immune strategies including XBP1/CD138/CS1 multipeptide vaccination, to enhance anti-tumor responses and improve patient outcome in MM.

Background: Endotheliopathy is a key element in COVID-19 pathophysiology, contributing to both morbidity and mortality. Biomarkers distinguishing different COVID-19 phenotypes from sepsis syndrome remain poorly understood. Objective: To characterize circulating biomarkers of endothelial damage in different COVID-19 clinical disease stages compared with sepsis syndrome and normal volunteers. Methods: Patients with COVID-19 pneumonia (n = 49) were classified into moderate, severe, or critical (life-threatening) disease. Plasma samples were collected within 48 to 72 h of hospitalization to analyze endothelial activation markers, including soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), von Willebrand Factor (VWF), A disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13 (ADAMTS-13) activity, thrombomodulin (TM), and soluble TNF receptor I (sTNFRI); heparan sulfate (HS) for endothelial glycocalyx degradation; C5b9 deposits on endothelial cells in culture and soluble C5b9 for complement activation; circulating dsDNA for neutrophil extracellular traps (NETs) presence, and alpha 2-antiplasmin and PAI-1 as parameters of fibrinolysis. We compared the level of each biomarker in all three COVID-19 groups and healthy donors as controls (n = 45). Results in critically ill COVID-19 patients were compared with other intensive care unit (ICU) patients with septic shock (SS, n = 14), sepsis (S, n = 7), and noninfectious systemic inflammatory response syndrome (NI-SIRS, n = 7). Results: All analyzed biomarkers were increased in COVID-19 patients versus controls (P < 0.001), except for ADAMTS-13 activity that was normal in both groups. The increased expression of sVCAM-1, VWF, sTNFRI, and HS was related to COVID-19 disease severity (P < 0.05). Several differences in these parameters were found between ICU groups: SS patients showed significantly higher levels of VWF, TM, sTNFRI, and NETS compared with critical COVID-19 patients and ADAMTS-13 activity was significantly lover in SS, S, and NI-SIRS versus critical COVID-19 (P < 0.001). Furthermore, alpha 2-antiplasmin activity was higher in critical COVID-19 versus NI-SIRS (P < 0.01) and SS (P < 0.001), whereas PAI-1 levels were significantly lower in COVID-19 patients compared with NI-SIRS, S, and SS patients (P < 0.01). Conclusions: COVID-19 patients present with increased circulating endothelial stress products, complement activation, and fibrinolytic dysregulation, associated with disease severity. COVID-19 endotheliopathy differs from SS, in which endothelial damage is also a critical feature of pathobiology. These biomarkers could help to stratify the severity of COVID-19 disease and may also provide information to guide specific therapeutic strategies to mitigate endotheliopathy progression.

This essay projects how a plague may be transformed into post-infection resilience. Peering into the future after Covid-19 has subsided, global heating and the burgeoning demands of the population ...

Patients with COVID-19 present a wide spectrum of disease severity, from asymptomatic cases in the majority to serious disease leading to critical care and even death. Clinically, four different scenarios occur within the typical disease timeline: first, an incubation and asymptomatic period; second, a stage with mild symptoms due mainly to the virus itself; third, in up to 20% of the patients, a stage with severe symptoms where a hyperinflammatory response with a cytokine storm driven by host immunity induces acute respiratory distress syndrome; and finally, a post-acute sequelae (PASC) phase, which present symptoms that can range from mild or annoying to actually quite incapacitating. Although the most common manifestation is acute respiratory failure of the lungs, other organs are also frequently involved. The clinical manifestations of the COVID-19 infection support a key role for endothelial dysfunction in the pathobiology of this condition. The virus enters into the organism via its interaction with angiotensin-converting enzyme 2-receptor that is present prominently in the alveoli, but also in endothelial cells, which can be directly infected by the virus. Cytokine release syndrome can also drive endothelial damage independently. Consequently, a distinctive feature of SARS-CoV-2 infection is vascular harm, with severe endothelial injury, widespread thrombosis, microangiopathy, and neo-angiogenesis in response to endothelial damage. Therefore, endothelial dysfunction seems to be the pathophysiological substrate for severe COVID-19 complications. Biomarkers of endothelial injury could constitute strong indicators of disease progression and severity. In addition, the endothelium could represent a very attractive target to both prevent and treat these complications. To establish an adequate therapy, the underlying pathophysiology and corresponding clinical stage should be clearly identified. In this review, the clinical features of COVID-19, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelium in COVID-19 patients are addressed.

This paper presents a compressed sensing (CS) based encryption scheme for wireless neural recording. An ultrahigh efficiency was achieved by leveraging CS for simultaneous data compression and encryption. CS enables sub-Nyquist sampling of neural signals by taking advantage of their intrinsic sparsity, while the CS process simultaneously encrypts the data with the sampling matrix being the cryptographic key. To share the key over an insecure wireless channel, we implemented an elliptic-curve cryptography (ECC) based key exchanging protocol. Local key shuffle and updating were adopted to eliminate the risks of potential information leakage. CS was executed in an application-specific integrated circuits (ASIC) fabricated in 180nm CMOS technology. Mixed-signal circuits were designed to optimize the power efficiency of the matrix-vector multiplication (MVM) of the CS operation. The ECC was implemented in a low-power Cortex-M0 based microcontroller (MCU). To be protected from timing attacks, the implementation avoided possible data-dependent branches. A wireless neural recorder prototype has been developed to demonstrate the proposed scheme. The prototype achieved an $8\times$ data rate reduction and a $35\times$ power saving compared with conventional implementation. The overall power consumption of ASIC and MCU was $442\mu \text{W}$ during the encrypted wireless transmission. The average correlated coefficient between the reconstructed signals and the uncompressed signals was 0.973, while the ciphertext-only attacks (CoA) achieved no better than 0.054 over 200,000 attacks. This work demonstrates a promising data compression and encryption scheme that can be used in a wide range of low-power signal recording systems with security requirements.

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P P

This article presents an implantable low-power wireless integrated system for tactile sensing applications. The reported application-specified integrated circuit (ASIC) uses a low-loss magnetic human body communication channel for both wireless power and data transfer. The chip is hybrid-integrated with an in-house fabricated MEMS capacitive force sensor to form an implantable artificial mechanoreceptor. An on-chip correlated double sampling capacitance to time converter (CTC) consumes 750 nW from a 1.2-V on-chip regulated supply, achieving a 2.0-fF resolution for an input capacitance of 14 pF and a FoM of 49 fJ/c-s while occupying an area of only 0.04 mm2. The CTC has a time-multiplexed mode to interface with four input capacitors. Wireless power management feedback is used to ensure robust operation in the presence of hand gesture changes and process–voltage–temperature variations. The on-chip data transmitter can operate in ON–OFF keying (OOK) or frequency-shift keying modulation formats, where it consumes only $7.8~\mu \text{W}$ in the OOK mode. The 1.62-mm2 chip is fabricated in a standard 180-nm CMOS process and consumes $110.3~\mu \text{W}$ .

Part B of this phase 1b study (ClinicalTrials.gov number, NCT02283775) evaluated safety and efficacy of a fixed-volume infusion of isatuximab, an anti-CD38 monoclonal antibody, in combination with pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma patients. Isatuximab (10 mg/kg weekly for 4 weeks, then every other week) was administered as a fixed-volume infusion of 250 mL (mL/h infusion rate) with standard doses of Pd on 28-day cycles. Patients (N = 47) had a median of three prior treatment lines (range, 1–8). Median duration of exposure was 36.9 weeks and median duration of first, second, and 3+ infusions were 3.7, 1.8, and 1.2 h, respectively. The most common non-hematologic treatment-emergent adverse events were fatigue (63.8%), infusion reactions (IRs), cough, and upper respiratory tract infection (40.4% each). IRs were all grade 2 and occurred only during the first infusion. The overall response rate was 53.2% in all patients (55.5% in response-evaluable population, 60.0% in daratumumab-naïve patients). Efficacy and safety findings were consistent with data from the isatuximab plus Pd infusion schedule in Part A of this study and also from the phase 3 ICARIA-MM study, and these new data confirm the safety, efficacy, and feasibility of fixed-volume infusion of isatuximab.