Methods for negating the impact of zinc contamination to allow characterization of positive allosteric modulators of glycine receptors.

Zinc is a ubiquitous contaminant in many buffers, purified products and common labware that has previously been suggested to impact on the results of functional GlyR studies and may inadvertently cause the effectiveness of some GlyR modulators to be over-estimated. This could greatly impact the assessment of potential drug-candidates and contribute to the reduced effectiveness of compounds that reach clinical stages. This is especially true for GlyR modulators being developed for pain therapeutics due to the changes in spinal zinc concentrations that have been observed during chronic pain conditions. In this study we use two-electrode voltage clamp electrophysiology to evaluate the metal chelators tricine and Ca-EDTA, and show that tricine produces inhibitory effects at GlyRα1 that are not mediated by zinc. We also utilized the zinc insensitive W170S mutation as a tool to validate metal chelators and confirm that zinc contamination has not impacted the examination of lipid modulators previously developed by our lab. This study helps to further develop methods to negate the impact of contaminating zinc in functional studies of GlyRs which should be incorporated into future studies that seek to characterize the activity of novel modulators at GlyRs.

Periodontitis is an immune-related adverse event associated with immune checkpoint inhibitors: A multi-center cohort study.

Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs) across various organ systems including oral health complications such as dry mouth and stomatitis. In this study, we aimed to determine the risk of periodontitis among patients on immune checkpoint inhibitors (ICIs) and to test the associations between ICI-associated periodontitis and other immune-related adverse events (irAEs). We performed a retrospective cohort study involving adult cancer patients between January 2010 and November 2021. Patients on an ICI were propensity score-matched to patients not on an ICI. The primary outcome was the occurrence of periodontitis. ICIs included programmed cell death 1 (PD-1) inhibitors programmed cell death ligand 1 (PD-L1) inhibitors, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. The risk of periodontitis following ICI use was derived through a Cox proportional hazard model and Kaplan-Meier survival analysis. Overall, 868 patients on an ICI were matched to patients not on an ICI. Among the ICI cohort, 41 (4.7%) patients developed periodontitis. The incidence rate of periodontitis was significantly higher in patients on an ICI than in patients not on an ICI (55.3 vs 25.8 per 100 patient-years, incidence rate ratio=2.14, 95% CI=1.38-3.33). Both the use of PD-L1 inhibitors (multivariate HR=2.5, 95%CI=1.3-4.7) and PD-1 inhibitors (multivariate HR=2.0, 95%CI=1.2-3.2) were associated with the risk of periodontitis. The presence of immune-related periodontitis was associated with better overall survival (not reached vs 17 months, log-rank p-value<0.001), progression-free survival (14.9 vs 5.6 months, log-rank p-value=0.01), and other concomitant immune-related cutaneous adverse events. In conclusion, ICI was associated with an increased risk of periodontitis. Immune-related periodontitis as an irAE was associated with better cancer survival and concomitant cutaneous irAEs.

Anti-spike antibody responses to SARS-CoV-2 mRNA vaccines in people with schizophrenia and schizoaffective disorder.

Importance: Individuals with schizophrenia are at higher risk for severe COVID-19 illness and severe breakthrough infection following vaccination. It is unclear whether immune response to vaccination differs in this population. Objective: To assess whether anti-SARS-CoV-2 spike antibody titers after vaccination differ in people with a diagnosis of schizophrenia or schizoaffective disorder (SZ) compared to controls without a psychiatric disorder. Design: This cohort study assessed antibody response following the first and second dose of mRNA vaccines at longitudinal timepoints, up to 7 weeks following the first dose of vaccine. Setting: A multi-center study including psychiatric healthcare settings in the United States and Europe. Participants: 205 adults with no history of COVID-19 infection, including 106 individuals with SZ and 99 controls without a psychiatric disorder, who received their first dose of SARS-CoV-2 mRNA vaccine between December 20, 2020 and May 27, 2021. Main outcomes and measures: Mean SARS-CoV-2 anti-Spike IgG antibody levels within 7 weeks after the first dose of vaccination. Results: A total of 205 individuals (mean [SD] age, 44.7 [12.0] years; 90 [43.9%] male) were included, of which 106 (51.7%) were diagnosed with SZ. SZ was associated with lower mean log antibody levels (-0.15; 95% CI, -0.27 to -0.03, P = 0.016) after adjusting for age, sex, body mass index, smoking, days since vaccination, and vaccine manufacturer. In secondary analyses of dose-specific responses, SZ was associated with a lower mean log antibody level after the second dose of vaccine (-0.23; 95% CI -0.39 to -0.06, P = 0.006), but not the first dose of vaccine (0.00; 95% CI -0.18- 0.19, P = 0.96). Conclusions and Relevance: In this cohort study of individuals with SZ and a control group without psychiatric disorders, SZ was associated with lower SARS-CoV-2 anti-spike antibody levels following 2 doses of SARS-CoV-2 mRNA vaccination. This highlights the need for further studies assessing vaccine immunogenicity in individuals with schizophrenia.

Automated workflows using Quantitative Colour Pattern Analysis (QCPA): a guide to batch processing and downstream data analysis.

Animal and plant colouration presents a striking dimension of phenotypic variation, the study of which has driven general advances in ecology, evolution, and animal behaviour. Quantitative Colour Pattern Analysis (QCPA) is a dynamic framework for analysing colour patterns through the eyes of non-human observers. However, its extensive array of user-defined image processing and analysis tools means image analysis is often time-consuming. This hinders the full use of analytical power provided by QCPA and its application to large datasets. Here, we offer a robust and comprehensive batch script, allowing users to automate many QCPA workflows. We also provide a complimentary set of useful R scripts for downstream data extraction and analysis. The presented batch processing extension will empower users to further utilise the analytical power of QCPA and facilitate the development of customised semi-automated workflows. Such quantitatively scaled workflows are crucial for exploring colour pattern spaces and developing ever-richer frameworks for analysing organismal colouration accounting for visual perception in animals other than humans. These advances will, in turn, facilitate testing hypotheses on the function and evolution of vision and signals at quantitative and qualitative scales, which are otherwise computationally unfeasible. Supplementary Information: The online version contains supplementary material available at 10.1007/s10682-024-10291-7.

Economical routes to size-specific assembly of self-closing structures.

Programmable self-assembly has seen an explosion in the diversity of synthetic crystalline materials, but developing strategies that target "self-limiting" assemblies has remained a challenge. Among these, self-closing structures, in which the local curvature defines the finite global size, are prone to polymorphism due to thermal bending fluctuations, a problem that worsens with increasing target size. Here, we show that assembly complexity can be used to eliminate this source of polymorphism in the assembly of tubules. Using many distinct components, we prune the local density of off-target geometries, increasing the selectivity of the tubule width and helicity to nearly 100%. We further show that by reducing the design constraints to target either the pitch or the width alone, fewer components are needed to reach complete selectivity. Combining experiments with theory, we reveal an economical limit, which determines the minimum number of components required to create arbitrary assembly sizes with full selectivity.

Neuroimaging meta regression for coordinate based meta analysis data with a spatial model.

Coordinate-based meta-analysis combines evidence from a collection of neuroimaging studies to estimate brain activation. In such analyses, a key practical challenge is to find a computationally efficient approach with good statistical interpretability to model the locations of activation foci. In this article, we propose a generative coordinate-based meta-regression (CBMR) framework to approximate a smooth activation intensity function and investigate the effect of study-level covariates (e.g. year of publication, sample size). We employ a spline parameterization to model the spatial structure of brain activation and consider four stochastic models for modeling the random variation in foci. To examine the validity of CBMR, we estimate brain activation on 20 meta-analytic datasets, conduct spatial homogeneity tests at the voxel level, and compare the results to those generated by existing kernel-based and model-based approaches. Keywords: generalized linear models; meta-analysis; spatial statistics; statistical modeling.

Resolving chaperone-assisted protein folding on the ribosome at the peptide level.

Protein folding in vivo begins during synthesis on the ribosome and is modulated by molecular chaperones that engage the nascent polypeptide. How these features of protein biogenesis influence the maturation pathway of nascent proteins is incompletely understood. Here, we use hydrogen-deuterium exchange mass spectrometry to define, at peptide resolution, the cotranslational chaperone-assisted folding pathway of Escherichia coli dihydrofolate reductase. The nascent polypeptide folds along an unanticipated pathway through structured intermediates not populated during refolding from denaturant. Association with the ribosome allows these intermediates to form, as otherwise destabilizing carboxy-terminal sequences remain confined in the ribosome exit tunnel. Trigger factor binds partially folded states without disrupting their structure, and the nascent chain is poised to complete folding immediately upon emergence of the C terminus from the exit tunnel. By mapping interactions between the nascent chain and ribosomal proteins, we trace the path of the emerging polypeptide during synthesis. Our work reveals new mechanisms by which cellular factors shape the conformational search for the native state.

Hindlimb immobilization induces insulin resistance and elevates mitochondrial ROS production in the hippocampus of female rats.

Alzheimer's Disease (AD) is the 5th leading cause of death in older adults and treatment options are severely lacking. Recent findings demonstrate a strong relationship between skeletal muscle and cognitive function, with evidence supporting that muscle quality and cognitive function are positively correlated in older adults. Conversely, decreased muscle function is associated with a 3-fold increased risk of cognitive decline. Based on these observations, the purpose of this study was to investigate the negative effects of muscle disuse (via a model of hindlimb immobilization (HLI)) on hippocampal insulin sensitivity and mitochondrial function and identify the potential mechanisms involved. HLI for 10 days in 4-month-old female Wistar rats resulted in the following novel findings: 1) hippocampal insulin resistance and deficits in whole body glucose homeostasis, 2) dramatically increased mitochondrial reactive oxygen species (ROS) production in the hippocampus, 3) elevated markers for amyloidogenic cleavage of APP and tau protein in the hippocampus, 4) and reduced BDNF expression. These findings were associated with global changes in iron homeostasis, with muscle disuse producing muscle iron accumulation in association with decreased serum and whole brain iron levels. We report the novel finding that muscle disuse alters brain iron homeostasis and reveal a strong negative correlation between muscle and brain iron content. Overall, HLI-induced muscle disuse has robust negative effects on hippocampal insulin sensitivity and ROS production in association with altered brain iron homeostasis. This work provides potential novel mechanisms that may help explain how loss of muscle function contributes to cognitive decline and AD risk.

Absence of effects of widespread badger culling on tuberculosis in cattle.

Government policy in England aims for the elimination of bovine tuberculosis (bTB). This policy includes culling of European badger (Meles meles) to reduce cattle TB incidence. The rationale is based on a field trial, the Randomised Badger Culling Trial (RBCT) 1998-2005, which reported a substantial decrease in bTB herd incidence where badger culling had been implemented, in comparison to untreated control areas. The RBCT was undertaken because previous studies of reductions in badgers by culling, reported a possible association between bTB in badger and cattle, but none could directly show causation. The effect of intensive widespread (proactive) culling in the RBCT was reported in 2006 in the journal Nature. Analysis of an extensive badger removal programme in England since 2013 has raised concerns that culling has not reduced bTB herd incidence. The present study re-examined RBCT data using a range of statistical models. Most analytical options showed no evidence to support an effect of badger culling on bTB herd incidence 'confirmed' by visible lesions and/or bacterial culture post mortem following a comparative intradermal skin test (SICCT). However, the statistical model chosen by the RBCT study was one of the few models that showed an effect. Various criteria suggest that this was not an optimal model, compared to other analytical options available. The most likely explanation is that the RBCT proactive cull analysis over-fitted the data with a non-standard method to control for exposure giving it a poor predictive value. Fresh appraisal shows that there was insufficient evidence to conclude RBCT proactive badger culling affected bTB breakdown incidence. The RBCT found no evidence of an effect of culling on 'total' herd incidence rates. Total herd incidences include those confirmed as bTB at necropsy and those herds where there was at least one animal animal positive to the comparative intradermal skin test, the standard diagnostic test used for routine surveillance, but not confirmed at necropsy. This was also the case using the more suitable statistical models. Use only of 'confirmed' herd incidence data, together with a more recent (2013) published perception that RBCT data presented 'a strong evidence base….with appropriate detailed statistical or other quantitative analysis' should be reconsidered. The results of the present report are consistent with other analyses that were unable to detect any disease control benefits from badger culling in England (2013-2019). This study demonstrates one form of potential driver to the reproducibility crisis, in this case with disease control management in an increasingly intensified livestock industry.

Protease Expression in the Human and Rat Cumulus Oocyte Complex (COC) During the Periovulatory Period: A Role in COC Migration.

The migratory and matrix-invading capacities of the cumulus oocyte complex (COC) have been shown to be important for the ovulatory process. In metastatic cancers, these capacities are due to increased expression of proteases, however, there is limited information on protease expression in the COCs. The present study examined COC expression of plasmins, matrix metalloproteases (MMP) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) family members in the rat and human. In the rat, hCG administration increased COC expression of Mmp2, Mmp9, Mmp13, Mmp14, Mmp16, Adamts1, and the protease inhibitors Timp1, Timp3 and Serpine1 by 8-12 hours. This ovulatory induction of proteases in vivo could be mimicked by forskolin and ampiregulin treatment of cultured rat COCs with increases observed in Mmp2, Mmp13, Mmp14, Mmp16, Mmp19, Plat, and the protease inhibitors Timp1, Timp3 and Serpine1. Comparison of expression between rat COCs and granulosa cells at the time of ovulation showed decreased Mmp9 and increased Mmp13, Mmp14, Mmp16, Adamts1, Timp1 and Timp3 expression in the COCs. In human, comparison of expression between cumulus and granulosa cells at the time of IVF retrieval showed decreased MMP1, MMP2, MMP9, and ADAMTS1, while expression of MMP16, TIMP1, and TIMP3 were increased. Treatment of expanding rat COCs with a broad spectrum MMP inhibitor, GM6001, significantly reduced the migration of cumulus cells in vitro. These data provide evidence that multiple proteases and their inhibitors are expressed in the COCs and play an important role in imparting the migratory phenotype of the COCs at the time of ovulation.

Activity of DNA polymerase κ across the genome in human fibroblasts.

DNA polymerase κ (Polκ) is a specialized polymerase that has multiple cellular roles such as translesion DNA synthesis, replication of repetitive sequences, and nucleotide excision repair. We have developed a method for capturing DNA synthesized by Polκ utilizing a Polκ-specific substrate, N2-(4-ethynylbenzyl)-2'-deoxyguanosine (EBndG). After shearing of the DNA into 200 to 500 bp lengths, the EBndG-containing DNA was covalently bound to biotin using the Cu(I)-catalyzed alkyne-azide cycloaddition reaction and isolated with streptavidin beads. Isolated DNA was then ligated to adaptors, followed by PCR amplification and next-generation sequencing to generate genome-wide repair maps. We have termed this method polymerase κ sequencing. Here, we present the human genome maps for Polκ activity in an undamaged cell line. We found that Polκ activity was enhanced in GC-rich regions, euchromatin regions, the promoter of genes, and in DNA that is replicated early in the S phase.

Symmetry-Guided Inverse Design of Self-Assembling Multiscale DNA Origami Tilings.

Recent advances enable the creation of nanoscale building blocks with complex geometries and interaction specificities for self-assembly. This nearly boundless design space necessitates design principles for defining the mutual interactions between multiple particle species to target a user-specified complex structure or pattern. In this article, we develop a symmetry-based method to generate the interaction matrices that specify the assembly of two-dimensional tilings, which we illustrate using equilateral triangles. By exploiting the allowed 2D symmetries, we develop an algorithmic approach by which any periodic 2D tiling can be generated from an arbitrarily large number of subunit species, notably addressing an unmet challenge of engineering 2D crystals with periodicities that can be arbitrarily larger than the subunit size. To demonstrate the utility of our design approach, we encode specific interactions between triangular subunits synthesized by DNA origami and show that we can guide their self-assembly into tilings with a wide variety of symmetries, using up to 12 unique species of triangles. By conjugating specific triangles with gold nanoparticles, we fabricate gold-nanoparticle supracrystals whose lattice parameter spans up to 300 nm. Finally, to generate economical design rules, we compare the design economy of various tilings. In particular, we show that (1) higher symmetries allow assembly of larger unit cells with fewer subunits and (2) linear supracrystals can be designed more economically using linear primitive unit cells. This work provides a simple algorithmic approach to designing periodic assemblies, aiding in the multiscale assembly of supracrystals of nanostructured "meta-atoms" with engineered plasmonic functions.

Adjunctive therapy with an oral H2S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction.

BACKGROUND AND PURPOSE: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S donor in two preclinical models of cardiometabolic HFpEF was investigated. EXPERIMENTAL APPROACH: Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H2S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or SGLT2i and SG1002 for 8 weeks. SG1002 monotherapy was investigated in additional animals. Cardiac function (echocardiography and haemodynamics), exercise capacity, glucose handling and multiorgan pathology were monitored during experimental protocols. KEY RESULTS: SGLT2i treatment improved E/e' ratio and treadmill exercise in both models. Combination therapy afforded increases in cardiovascular sulphur bioavailability that coincided with improved left end-diastolic function (E/e' ratio), exercise capacity, metabolic state, cardiorenal fibrosis, and hepatic steatosis. Follow-up studies with SG1002 monotherapy revealed improvements in diastolic function, exercise capacity and multiorgan histopathology. CONCLUSIONS AND IMPLICATIONS: SGLT2i monotherapy remediated pathological complications exhibited by two well-established HFpEF models. Adjunctive H2S therapy resulted in further improvements of cardiometabolic perturbations beyond SGLT2i monotherapy. Follow-up SG1002 monotherapy studies inferred an improved phenotype with combination therapy beyond either monotherapy. These data demonstrate the differing effects of SGLT2i and H2S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.

Efficient exact exchange using Wannier functions and other related developments in planewave-pseudopotential implementation of RT-TDDFT.

The plane-wave pseudopotential (PW-PP) formalism is widely used for the first-principles electronic structure calculation of extended periodic systems. The PW-PP approach has also been adapted for real-time time-dependent density functional theory (RT-TDDFT) to investigate time-dependent electronic dynamical phenomena. In this work, we detail recent advances in the PW-PP formalism for RT-TDDFT, particularly how maximally localized Wannier functions (MLWFs) are used to accelerate simulations using the exact exchange. We also discuss several related developments, including an anti-Hermitian correction for the time-dependent MLWFs (TD-MLWFs) when a time-dependent electric field is applied, the refinement procedure for TD-MLWFs, comparison of the velocity and length gauge approaches for applying an electric field, and elimination of long-range electrostatic interaction, as well as usage of a complex absorbing potential for modeling isolated systems when using the PW-PP formalism.

Fast Outer-Sphere Electron Transfer and High Specific Capacitance at Covalently Modified Carbon Electrodes.

Carbon electrodes typically display sluggish electron transfer kinetics due to the adsorption of adventitious molecules that effectively insulate the surface. Here, we describe a method for rendering graphitic carbon electrodes permanently hydrophilic by functionalization with 4-(diazonium)benzenesulfonic acid. In aqueous electrolytes, these hydrophilic carbon electrodes exhibit metal-like specific capacitance (∼40 µF/cm2) as measured by cyclic voltammetry, suggesting a change in the double-layer structure at the carbon surface. Additionally, the modified electrodes show fast charge transfer kinetics to outer-sphere one-electron redox couples such as ferro-/ferricyanide as well as improved electron transfer kinetics in alkaline aqueous redox flow batteries.

Infectivity of Plasmodium parasites to Aedes aegypti and Anopheles stephensi mosquitoes maintained on blood-free meals of SkitoSnack.

BACKGROUND: Aedes and Anopheles mosquitoes are responsible for tremendous global health burdens from their transmission of pathogens causing malaria, lymphatic filariasis, dengue, and yellow fever. Innovative vector control strategies will help to reduce the prevalence of these diseases. Mass rearing of mosquitoes for research and support of these strategies presently depends on meals of vertebrate blood, which is subject to acquisition, handling, and storage issues. Various blood-free replacements have been formulated for these mosquitoes, but none of these replacements are in wide use, and little is known about their potential impact on competence of the mosquitoes for Plasmodium infection. METHODS: Colonies of Aedes aegypti and Anopheles stephensi were continuously maintained on a blood-free replacement (SkitoSnack; SS) or bovine blood (BB) and monitored for engorgement and hatch rates. Infections of Ae. aegypti and An. stephensi were assessed with Plasmodium gallinaceum and P. falciparum, respectively. RESULTS: Replicate colonies of mosquitoes were maintained on BB or SS for 10 generations of Ae. aegypti and more than 63 generations of An. stephensi. The odds of engorgement by SS- relative to BB-maintained mosquitoes were higher for both Ae. aegypti (OR = 2.6, 95% CI 1.3-5.2) and An. stephensi (OR 2.7, 95% CI 1.4-5.5), while lower odds of hatching were found for eggs from the SS-maintained mosquitoes of both species (Ae. aegypti OR = 0.40, 95% CI 0.26-0.62; An. stephensi OR = 0.59, 95% CI 0.36-0.96). Oocyst counts were similar for P. gallinaceum infections of Ae. aegypti mosquitoes maintained on SS or BB (mean ratio = [mean on SS]/[mean on BB] = 1.11, 95% CI 0.85-1.49). Similar oocyst counts were also observed from the P. falciparum infections of SS- or BB-maintained An. stephensi (mean ratio = 0.76, 95% CI 0.44-1.37). The average counts of sporozoites/mosquito showed no evidence of reductions in the SS-maintained relative to BB-maintained mosquitoes of both species. CONCLUSIONS: Aedes aegypti and An. stephensi can be reliably maintained on SS over multiple generations and are as competent for Plasmodium infection as mosquitoes maintained on BB. Use of SS alleviates the need to acquire and preserve blood for mosquito husbandry and may support new initiatives in fundamental and applied research, including novel manipulations of midgut microbiota and factors important to the mosquito life cycle and pathogen susceptibility.

Data hazards in synthetic biology.

Data science is playing an increasingly important role in the design and analysis of engineered biology. This has been fueled by the development of high-throughput methods like massively parallel reporter assays, data-rich microscopy techniques, computational protein structure prediction and design, and the development of whole-cell models able to generate huge volumes of data. Although the ability to apply data-centric analyses in these contexts is appealing and increasingly simple to do, it comes with potential risks. For example, how might biases in the underlying data affect the validity of a result and what might the environmental impact of large-scale data analyses be? Here, we present a community-developed framework for assessing data hazards to help address these concerns and demonstrate its application to two synthetic biology case studies. We show the diversity of considerations that arise in common types of bioengineering projects and provide some guidelines and mitigating steps. Understanding potential issues and dangers when working with data and proactively addressing them will be essential for ensuring the appropriate use of emerging data-intensive AI methods and help increase the trustworthiness of their applications in synthetic biology.

Evaluating Lab-Based Eligibility Criteria by Race/Ethnicity in Clinical Trials of Diffuse Large B-Cell Lymphoma.

Underrepresentation of racial and ethnic subgroups in cancer clinical trials remains a persistent challenge. Restrictive clinical trial eligibility criteria have been shown to exacerbate this problem. We previously identified that up to 24% of patients treated with standard immunochemotherapy (IC) would have been excluded from recent first-line trials in diffuse large B-cell lymphoma (DLBCL) based on 5 lab-based criteria. These ineligible patients had worse clinical outcomes and increased deaths related to lymphoma progression suggesting the potential exclusion of patients who could have benefited most from the novel therapies being evaluated. Utilizing data from the prospectively enrolled Lymphoma Epidemiology Outcomes (LEO) Cohort study, with demographics broadly similar to the U.S. patients diagnosed with lymphoma, we evaluated the impact of laboratory eligibility criteria from recent first-line DLBCL trials across various racial and ethnic backgrounds. There were significant differences in the baseline lab values by race/ethnicity with Black/African American (AA) patients having the lowest mean hemoglobin and highest creatinine clearance. Based on recent clinical trial eligibility criteria, AA and Hispanic patients had higher rates of lab-based ineligibility compared to Non-Hispanic Whites. The largest gap in the clinical outcomes between eligible (ref) and non-eligible patients was noted within AA patients with an overall survival hazard ratio based on POLARIX clinical trial criteria of 4.09, 95% CI: 1.83-9.14. A thoughtful approach to the utility of each criterion and cut offs for eligibility needs to be evaluated in the context of its differential impact across various racial/ethnic groups.

Phase 2 Trial of the Farnesyltransferase Inhibitor Tipifarnib for Relapsed/Refractory Peripheral T Cell Lymphoma.

A phase 2, international, open-label, non-randomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary endpoint was objective response rate (ORR); secondary endpoints included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n=38 angioimmunoblastic T-cell lymphoma (AITL), n=25 PTCL not otherwise specified (PTCL-NOS), and n=2 other T-cell lymphomas. The ORR was 39.7% (95% CI, 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in AITL patients (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included: neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the non-responder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pre-treated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. ClinicalTrials.gov NCT02464228.