Subpopulation Of Patients Research Articles

Immune Reconstitution after BTKi Treatment in Chronic Lymphocytic Leukemia

To analyze the immune reconstitution after BTKi treatment in patients with chronic lymphocytic leukemia (CLL). The clinical and laboratorial data of 59 CLL patients admitted from January 2017 to March 2022 in Fujian Medical University Union Hospital were collected and analyzed retrospectively. The median age of 59 CLL patients was 60.5(36-78). After one year of BTKi treatment, the CLL clones (CD5 +/CD19 +) of 51 cases (86.4%) were significantly reduced, in which the number of cloned-B cells decreased significantly from (46±6.1)×109/L to (2.3±0.4)×109/L (P =0.0013). But there was no significant change in the number of non-cloned B cells (CD19 + minus CD5 +/CD19 +). After BTKi treatment, IgA increased significantly from (0.75±0.09)g/L to (1.31±0.1)g/L (P <0.001), while IgG and IgM decreased from (8.1±0.2)g/L and (0.52±0.6)g/L to (7.1±0.1)g/L and (0.47±0.1)g/L, respectively (P <0.001, P =0.002). BTKi treatment resulted in a significant change in T cell subpopulation of CLL patients, which manifested as both a decrease in total number of T cells from (2.1±0.1)×109/L to (1.6±0.4)×109/L and NK/T cells from (0.11±0.1)×109/L to (0.07±0.01)×109/L (P =0.042, P =0.038), both an increase in number of CD4 + cells from (0.15±6.1)×109/L to (0.19±0.4)×109/L and CD8 + cells from (0.27±0.01)×109/L to (0.41±0.08)×109/L (both P <0.001). BTKi treatment also up-regulated the expression of interleukin (IL)-2 while down-regulated IL-4 and interferon (IFN)-γ. However, the expression of IL-6, IL-10, and tumor necrosis factor (TNF)-α did not change significantly. BTKi treatment could also restored the diversity of TCR and BCR in CLL patients, especially obviously in those patients with complete remission (CR) than those with partial remission (PR). Before and after BTKi treatment, Shannon index of TCR in patients with CR was 0.02±0.008 and 0.14±0.001 (P <0.001), while in patients with PR was 0.01±0.03 and 0.05±0.02 (P >0.05), respectively. Shannon index of BCR in patients with CR was 0.19±0.003 and 0.33±0.15 (P <0.001), while in patients with PR was 0.15±0.009 and 0.23±0.18 (P <0.05), respectively. BTKi treatment can shrink the clone size in CLL patients, promote the expression of IgA, increase the number of functional T cells, and regulate the secretion of cytokines such as IL-2, IL-4, and IFN-γ. BTKi also promote the recovery of diversity of TCR and BCR. BTKi treatment contributes to the reconstitution of immune function in CLL patients.

Aspirin for the Primary Prevention of Cardiovascular Diseases in Patients with Chronic Kidney Disease: An Updated Meta-analysis.

Chronic kidney disease is associated with increased risk of cardiovascular diseases (CVD). This meta-analysis aims to evaluate the efficacy and safety of aspirin administered for primary prevention of CVD in patients with chronic kidney disease. PubMed, Scopus, Web of Science, CENTRAL and Clinicaltrials.gov were systematically searched from inception to 22 June 2023. Randomized controlled trials (RCTs) and cohort studies evaluating aspirin as primary prevention of CVD in chronic kidney disease were included. Meta-analysis was conducted using random-effects models. Overall, 11 studies (6 RCTs and 5 cohort studies) with 24,352 patients were included. The meta-analysis of RCTs indicated that aspirin was associated with lower risk of major adverse cardiovascular events [hazard ratio (HR): 0.79; 95% confidence intervals (CI): 0.64-0.97] and higher risk of major bleeding [risk ratio (RR): 1.35; 95% CI 1.15-1.58]. Incorporating observational evidence led to statistically non-significant findings in terms of risk of both cardiovascular events (pooled HR: 0.97; 95% CI 0.75-1.25; low certainty) and major bleeding (pooled RR: 1.21; 95% CI 0.99-1.48; moderate certainty). No statistically significant differences between aspirin and placebo were observed in the outcomes of mortality, coronary heart disease, stroke and renal events. RCT evidence points to a possible benefit in cardiovascular event reduction from aspirin administration, at the cost of increased major bleeding risk. This finding was not confirmed when the existing observational evidence was incorporated. Further research should determine the most appropriate subpopulation of chronic kidney disease patients that would benefit the most from prophylactic aspirin therapy. The study protocol has been prospectively registered and is publicly available from: https://doi.org/10.17504/protocols.io.261ged63jv47/v1 .

Real-world efficacy and toxicity of ipilimumab and nivolumab as first line treatment of metastatic renal cell carcinoma (mRCC) in a subpopulation of elderly and poor performance status patients.

367 Background: Ipilimumab and nivolumab (ipi/nivo) improved overall survival (OS) and response rates compared to sunitinib in the pivotal Checkmate 214 trial of intermediate/poor risk mRCC. A subgroup analysis showed no significant difference in OS for ipi/nivo in pts 65 to 75 years old (yo), as well as pts &gt;75 yo. In another subgroup analysis, Karnofsky performance status (KPS) &lt;70 was associated with worse median OS compared with pts with KPS ≥ 70. We evaluated efficacy and toxicity of ipi/nivo in an older and frailer population in a real-world cohort. Methods: Analysis was conducted on a real-world cohort with mRCC (N=378) treated with ipi/nivo as first line treatment from the Canadian Kidney Cancer Information System (CKCis) database from January 2011 to March 2022. Median follow-up was 14.3 m (range 0 to 87.6). A comparison was made between outcomes and toxicity in pts ≥ versus (vs) &lt;70 yo, ≥ vs &lt;75 yo, KPS &lt; vs ≥70, and ≥70 yo with KPS &lt;70 vs &lt;70 yo with KPS &gt;70. Toxicity was graded as per CTCAE v4.03 or any toxicity that resulted in a dose/schedule change. OS, progression free survival (PFS) and time to treatment failure (TTF) were calculated by Kaplan-Meier analysis. Log rank tests were used for comparison between groups. Multivariate analysis was done including IMDC for all outcomes. Results: Median OS was worse in older patients at 30.0 m in pts ≥ 70 yo vs 45.4 m in pts &lt; 70 yo (p=0.060), and 19.0 m in the pts ≥ 75 yo vs 45.5 m in pts &lt; 75 yo (p=0.003) despite similar disease control rates and toxicity. Median PFS was similar in younger and older pts: &lt; vs ≥ 70 yo (p=0.560) and &lt; vs ≥ 75 yo (p=0.296). Median TTF was comparable in &lt; 70 yo and ≥ 70 yo (p=0.106) and &lt; 75 and ≥ 75 yo groups (p-value=0.733). Median OS, PFS and TTF were comparable in pts KPS &lt; 70 vs pts KPS ≥ 70 and in pts ≥70 yo with KPS &lt; 70 vs pts &lt; 70 yo with KPS &gt;70. Adjusted and unadjusted analysis showed no difference in OS and PFS between groups. Conclusions: Use of ipi/nivo in mRCC in older patients was associated with inferior OS, while decreased performance status had equivalent OS. Both groups had equivalent TTF and PD without higher toxicity. We believe that ipi/nivo is a reasonable treatment option for older and low performance status patients. [Table: see text]

Risk model based on genes regulating the response of tumor cells to T-cell-mediated killing in esophageal squamous cell carcinoma.

Immune checkpoint inhibitors (ICIs) represent a promising therapeutic approach for esophageal squamous cell carcinoma (ESCC). However, the subpopulations of ESCC patients expected to benefit from ICIs have not been clearly defined. The anti-tumor cytotoxic activity of T cells is an important pharmacological mechanism of ICIs. In this study, the prognostic value of the genes regulating tumor cells to T cell-mediated killing (referred to as GRTTKs) in ESCC was explored by using a comprehensive bioinformatics approach. Training and validation datasets were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. A prognostic risk scoring model was developed by integrating prognostic GRTTKs from TCGA and GEO datasets using a ridge regression algorithm. Patients with ESCC were divided into high- and low-risk groups based on eight GRTTKs (EIF4H, CDK2, TCEA1, SPTLC2, TMEM209, RGP1, EIF3D, and CAPZA3) to predict overall survival in the TCGA cohort. Using Kaplan-Meier curves, receiver operating characteristic curves, and C-index analysis, the high reliability of the prognostic risk-scoring model was certified. The model scores served as independent prognostic factors, and combining clinical staging with risk scoring improved the predictive value. Patients in the high-risk group exhibited abundant immune cell infiltration, including immune checkpoint expression, antigen presentation capability, immune cycle gene expression, and high tumor inflammation signature scores. The high-risk group exhibited a greater response to immunotherapy and neoadjuvant chemotherapy than the low-risk group. Drug sensitivity analysis demonstrated lower IC50 for AZD6244 and PD.0332991 in high-risk groups and lower IC50 for cisplatin, ATRA, QS11, and vinorelbine in the low-risk group. Furthermore, the differential expression of GRTTK-related signatures including CDK2, TCEA1, and TMEM209 were verified in ESCC tissues and paracancerous tissues. Overall, the novel GRTTK-based prognostic model can serve as indicators to predict the survival status and immunotherapy response of patients with ESCC, thereby providing guidance for the development of personalized treatment strategies.

Abstract WMP5: Intravenous Thrombolysis Before Thrombectomy Improves Functional Outcome After Stroke Independent of Reperfusion Grade

Background: We studied the effect of intravenous thrombolysis (IVT) before thrombectomy for anterior circulation large vessel occlusion (acLVO) on functional outcome and scrutinized its dependence on grade of reperfusion and distal thrombus migration. Methods: We included consecutive acLVO patients from our prospective registry of thrombectomy-eligible patients treated from 01/01/2017 to 01/01/2023 at a tertiary stroke center in Germany into a retrospective cohort study. We evaluated the effects of IVT on functional outcome quantified via modified Rankin scale (mRS) at 90 days applying multivariable logistic and lasso regression including interaction terms with grade of reperfusion quantified via modified Thrombolysis in Cerebral Infarction (mTICI) scale and distal thrombus migration adjusted for demographic and cardiovascular risk profiles, clinical and imaging stroke characteristics and onset-to-recanalization time. We performed sensitivity analysis using propensity score matching. Results: In our study population of 1000 thrombectomy-eligible patients (513 females, median age 77 [67-84, interquartile range]) IVT emerged as predictor of favorable functional outcome (mRS 0-2) independent of mTICI (adjusted OR 0.49; 95% CI [0.32;0.75]; p=0.001). In those who underwent thrombectomy (n=812) the association of IVT and favorable functional outcome was reproduced (adjusted OR 0.49; 95% CI [0.31;0.74]; p=0.001) and was further confirmed on propensity score analysis where IVT led to a 0.35-point decrease in 90-day mRS score [ß=-0.35; 95CI% [-0.68;-0.01]; p=0.04]. The additive benefit of IVT remained independent of mTICI (ß=-1.79; 95% CI [-3.43;-0.15]; p=0.03) and distal thrombus migration (ß=-0.41; 95% CI [-0.69;-0.13]; p=0.004) on interaction analysis. Consequently, IVT showed an additive effect on functional outcome in the subpopulation of thrombectomy patients who achieved successful reperfusion (TICI≥2b; ß=-0.46; 95% CI [-0.74;-0.17]; p=0.002) and remained beneficial in those with unsuccessful reperfusion (TICI≤2a; ß=-0.47; 95% CI [-0.96;-0.01]; p=0.05). Conclusions: In thrombectomy-eligible acLVO patients IVT improves functional outcome independent of grade of reperfusion and distal thrombus migration.

Bone Mineral Density is Related to CD4+ T Cell Counts and Muscle Mass is Associated with B Cells in Common Variable Immunodeficiency Patients.

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by chronic/recurrent respiratory infections, bronchiectasis, autoimmunity, inflammatory, gastrointestinal diseases and malignancies associated with a chronic inflammatory state and increased risk of osteoporosis and muscle loss. The aim of this study was to evaluate bone mineral density (BMD), body composition and their relationship with lymphocyte subpopulations in CVID patients. Dual-energy X-ray absorptiometry was performed to assess BMD, lean mass, and fat mass in CVID patients. Peripheral blood CD4+, CD8+, and CD19+ cells were measured using flow cytometry. Thirty-three patients (37.3 ± 10.8 years old) were examined. Although only 11.8% of the individuals were malnourished (BMI <18.5 kg/m2), 27.7% of them had low skeletal muscle mass index (SMI), and 57.6% of them had low BMD. Patients with osteopenia/osteoporosis presented lower weight (p = 0.007), lean mass (p = 0.011), appendicular lean mass (p = 0.011), SMI (p = 0.017), and CD4+ count (p = 0.030). Regression models showed a positive association between CD4+ count and bone/muscle parameters, whereas CD19+ B cell count was only associated with muscle variables. Analysis of ROC curves indicated a cutoff value of CD4+ count (657 cells/mm3; AUC: 0.71, 95% CI 0.52-0.90) which was related to low BMD. Weight (p = 0.004), lean mass (p = 0.027), appendicular lean mass (p = 0.022), SMI (p = 0.029), total bone mineral content (p = 0.005), lumbar (p = 0.005), femoral neck (p = 0.035), and total hip BMD (p<0.001) were found to be lower in patients with CD4+ count below the cutoff. CVID patients presented with low BMD, which was associated with CD4+ count. Moreover, low muscle parameters were correlated with B cell count.

Abstract TP68: Nina Campbell MSN BSN RN

Many of the American Heart Association’s Get with the Guidelines metrics for stroke are medication-related, including appropriate utilization of antithrombotics, statins, and anticoagulation. Furthermore, for the subpopulation of patients with type 2 diabetes, an antihyperglycemic medication with proven cardiovascular benefit is indicated. Abstraction to the American Heart Association Get with the Guidelines has clear but complex guidelines on criteria for meeting these metrics. Our goal was to improve adherence to the guidelines via pharmacist assessment, discussion, and documentation. Prior to December 2022, clinical pharmacists had been reviewing the use of antithrombotics, statins, and anticoagulation in stroke patients and reaching out to the provider with concerns. However, they were not yet reviewing the use of antihyperglycemic medications with proven cardiovascular benefit nor documenting assessments/rationale in the patient’s chart. In December 2022, pharmacists started evaluating antihyperglycemic medications with proven CVD benefits in addition to the above, with assessments taking place Monday through Friday. The pharmacist would reach out to the provider when necessary and also document rationale for appropriate avoidance of usual recommended therapy, if indicated. The most notable intervention was the creation of pre-formatted note with the various specific ways to meet each medication-related metric in accordance with Get with the Guidelines abstraction criteria. Baseline data from January to November 2022 indicated good adherence to the stroke metrics involving the use of antithrombotics, statins, and anticoagulation that pharmacy was already following at that time, ranging from 97.7-100% adherence. However, the metric of addressing an antihyperglycemic medication with proven CVD benefit was only met 47.1% of the time. After the above intervention, data collected from March to July of 2023 demonstrated a stable effect on the metrics that were already above goal, ranging 96.5% to 100%, but there was a significant increase in adherence to the antihyperglycemic medication with proven CVD benefit, which went from 47.1% to 83.3%.

A Combined Approach of Facial Neuromuscular Rehabilitation and Surgical Reconstruction in the Remediation of Facial Palsy: A Multidisciplinary Team Approach.

Facial neuromuscular rehabilitation (fNMR) is an evidence-based practice for the treatment of peripheral facial palsy (PFP). Surgical reconstruction can be indicated for patients who demonstrate poor or no recovery to support symmetry, function, and aesthesis. There is paucity of research demonstrating the therapeutic benefit of a multidisciplinary team (MDT) in facial recovery of this specific subpopulation of patients. This article will outline the role of specialist facial therapy in the remediation of PFP, focusing on those who undergo surgical reconstruction to optimize their facial recovery. Case studies are used to demonstrate surgical and therapeutic outcomes as well as the results of a patient survey conducted for a service evaluation. We discuss the role of the MDT in supporting recovery as well as the role of targeted fNMR. The term fNMR is often used interchangeably with facial therapy or facial rehabilitation. We will refer to fNMR as a technique of facial rehabilitation.We aim to demonstrate that an MDT approach to the treatment of people with facial palsy provides positive outcomes for this surgical population and that future research would be beneficial to support this service delivery model.

APC as a high-utility mutational biomarker that may identify subpopulations of patients with mutant RAS/BRAF and right-sided colorectal cancer (CRC) who derive benefit from EGFR inhibitors (EGFRi).

56 Background: Although, EGFRi including Cetuximab (CTX) and Panitumumab (PMB) is restricted to KRAS wild-type ( KRASWT) tumors, ~50% of patients still fail to respond to therapy. Using a transcriptional signature as a surrogate for cetuximab response, we previously reported that mutations in APC ( APCMUT) and TP53( TP53MUT) might predict cetuximab sensitivity, particularly in RASWT tumors (Yang M. et al., 2019). The current study aimed to use real world EGFRi treatment and survival data to independently validate these mutations as predictive, high-utility biomarkers of benefit to specific subpopulations of CRC. Methods: CTX/PMB-treated CRC specimens (n=1846) with clinical outcomes and NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). All analyses were performed in MSS tumors, determined by immunohistochemistry of MMR proteins and/or NGS. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RASMUT /BRAFMUT, or RASWT /BRAFWT if no mutation was detected for each gene. Survival on EGFRi was calculated from the initiation of EGFRi to last contact (E-OS) or last dose of EGFRi (E-TOT) using Kaplan-Meir method. Results: While concurrent TP53MUT/ APCMUT were associated with improved E-OS compared to TP53MUT alone (hazard ratio [HR]=0.565, p&lt;0.00001), APCMUT tumors were associated with improved E-OS independent of TP53 mutation status. Compared to APCWT, APCMUT were associated with longer E-OS in RAS/BRAF mutant as well as wild-type subpopulations and in left- and right- sided tumors. Furthermore, APCMUT were associated with improved E-TOT in PMB treated tumors independent of RAS/BRAF mutation status and tumor sidedness (HR range:0.59-0.75, all p&lt;0.05). Conclusions: Our data suggests that the simple application of a high-utility mutational biomarker ( APC), may increase the eligibility for successful EGFRi therapy in a substantial subpopulation of RAS/BRAF mt patients as well as right-sided CRC, potentially altering the standard of care. Further validation of this biomarker in a prospective clinical trial is warranted. [Table: see text]

Abstract B073: Understanding treatment response in pancreatic cancer: NetraAI provides genetic differentiation in FOLFIRINOX and gemcitabine response

Abstract Pancreatic cancer is known as a “silent killer” due to vague symptoms, late diagnosis, rapid progression, and poor response to therapy. Due to the highly malignant nature of this disease, prolonging progression-free survival (PFS) and overall survival (OS) for patients is critical. Standard of care involves combination chemotherapy using FOLFIRINOX (FFX) or Gemcitabine with nab-paclitaxel (GnP). The COMPASS trial performed whole genome sequencing (WGS) and RNA sequencing (RNASeq) on pancreatic ductal adenocarcinoma (PDAC) patients prior to FFX or GnP first-line combination therapy, finding molecular heterogeneity between patients and differing response to chemotherapy. Using the COMPASS trial dataset consisting of only 208 patients and NetraAI, a novel machine learning (ML) platform using a novel causal feature set discovery methodology, we explored generated hypotheses to differentiate causal factors that affect patient response to FFX and GnP. Differentiating FFX and GnP treatment response in stable disease patients revealed 3 distinct subpopulations with genetic differentiation related to neuron death and regulation, neurotrophin signaling, and neuron apoptotic processes. NetraAI identified genes driving patient subpopulations, such as LRRC8E, PTPRH, and UTG1A13p. Further investigation revealed that LRRC29 and CLEC19A distinguished a group of patients that responded well to FFX. LRRC29 relates to HOOK1, which negatively regulates epithelial-to-mesenchymal transition and has been reported to be decreased in PDAC. Low HOOK1 and SHP2 expression in non-small cell lung cancer is associated with a good response to GnP, suggesting that chemotherapy response depends on the interaction of the chemotherapeutic agent and genetic factors involved in disease progression as opposed to the tumor type. These results suggest that LRRC29 expression can act as a biomarker to choose between GnP and FFX treatment. In this way, NetraAI's ability to generate explainable hypotheses around patient subpopulations can help oncologists personalize treatments and better understand clinical trial patient populations. By identifying distinct genetic signatures within patient datasets. By identifying unique molecular heterogeneity that explains differing responses to therapy, NetraAI is a powerful tool that can extract insights from multi-dimensional and highly heterogenous patient population datasets that can help to inform clinical trial enrichment decisions to improve the success of pivotal trials. This work has a significant impact on precision medicine and clinical trial de-risking, while identifying specific genes and pathways involved in patient response to therapy. Citation Format: Bessi Qorri, Mike Tsay, Josh Spiegel, Douglas Cook, Joseph Geraci. Understanding treatment response in pancreatic cancer: NetraAI provides genetic differentiation in FOLFIRINOX and gemcitabine response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B073.

The Role of Proton Therapy for Prostate Cancer in the Setting of Hip Prosthesis.

Given that the current standard of proton therapy (PT) for prostate cancer is through bilateral beams, this modality is typically avoided when it comes to treatment of patients with hip prosthesis. The purpose of this study was to evaluate whether novel PT methods, i.e., anterior proton beams and proton arc therapy (PArc), could be feasible options to treat this patient subpopulation. We evaluate PT methods in the context of dosimetry and robustness and compare with standard of practice volumetric modulated arc therapy (VMAT) to explore any potential benefits. Two PT and one VMAT treatment plans were retrospectively created for 10 patients who participated in a clinical trial with a weekly repeat CT (rCT) imaging component. All plans were robustly optimized and featured: (1) combination anterior oblique and lateral proton beams (AoL), (2) PArc, and (3) VMAT. All patients had hydrogel spacers in place, which enabled safe application of anterior proton beams. The planned dose was 70 Gy (RBE) to the entire prostate gland and 50 Gy (RBE) to the proximal seminal vesicles in 28 fractions. Along with plan dose-volume metrics, robustness to setup and interfractional variations were evaluated using the weekly rCT images. The linear energy transfer (LET)-weighted dose was evaluated for PArc plans to ensure urethra sparing given the typical high-LET region at the end of range. Both PT methods were dosimetrically feasible and provided reduction of some key OAR metrics compared to VMAT except for penile bulb, while providing equally good target coverage. Significant differences in median rectum V35 (22-25%), penile bulb Dmean (5 Gy), rectum V61 (2%), right femoral head Dmean (5 Gy), and bladder V39 (4%) were found between PT and VMAT. All plans were equally robust to variations. LET-weighted dose in urethra was equivalent to the physical dose for PArc plans and hence no added urethral toxicity was expected. PT for treatment of prostate cancer patients with hip prosthesis is feasible and equivalent or potentially superior to VMAT in quality in some cases. The choice of radiotherapy regimen can be personalized based on patient characteristics to achieve the best treatment outcome.

The FOXP3+ Pro-Inflammatory T Cell: A Potential Therapeutic Target in Crohn’s Disease

Background and aimsThe incidence of Crohn’s disease (CD) continues to increase worldwide. The contribution of CD4+ cell populations remains to be elucidated. Here, we aim to provide an in-depth transcriptional assessment of CD4+ T cells driving chronic inflammation in CD. MethodsWe performed single cell RNA-sequencing in CD4+ T cells isolated from ileal biopsies of CD patients compared to healthy individuals. Cells underwent clustering analysis, followed by analysis of gene signalling networks. We overlapped our differentially expressed genes with publicly available microarray datasets and performed functional in vitro studies, including an in vitro suppression assay and organoid systems, to model gene expression changes observed in CD TREGs and to test predicted therapeutics. ResultsWe identified five distinct FOXP3+ regulatory T (Treg) subpopulations. Tregs isolated from healthy controls represent the origin of pseudotemporal development into inflammation-associated subtypes. These proinflammatory Tregs displayed a unique responsiveness to TNFα signaling with impaired suppressive activity in vitro and an elevated cytokine response in an organoid co-culture system. As predicted in silico, the histone deacetylase inhibitor Vorinostat normalized gene expression patterns, rescuing the suppressive function of FOXP3+ cells in vitro. ConclusionWe identified a novel, proinflammatory FOXP3+ T cell subpopulation in CD patients and developed a pipeline to specifically target these cells using the FDA-approved drug Vorinostat.

The Clinical Development of Taldefgrobep Alfa: An Anti-Myostatin Adnectin for the Treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans. Taldefgrobep alfa is an anti-myostatin recombinant protein engineered to bind to and block myostatin signaling. Preclinical studies of taldefgrobep alfa demonstrated significant decreases in myostatin and increased lower limb volume in three animal species, including dystrophic mice. This manuscript reports the cumulative data from three separate clinical trials of taldefgrobep alfa in DMD: a phase1 study in healthy adult volunteers (NCT02145234), and two randomized, double-blind, placebo-controlled studies in ambulatory boys with DMD-a phase1b/2 trial assessing safety (NCT02515669) and a phase2/3 trial including the North Star Ambulatory Assessment (NSAA) as the primary endpoint (NCT03039686). In healthy adult volunteers, taldefgrobep alfa was generally well tolerated and resulted in a significant increase in thigh muscle volume. Treatment with taldefgrobep alfa was associated with robust dose-dependent suppression of free myostatin. In the phase1b/2 trial, myostatin suppression was associated with a positive effect on lean body mass, though effects on muscle mass were modest. The phase2/3 trial found that the effects of treatment did not meet the primary endpoint pre-specified futility analysis threshold (change from baseline of ≥ 1.5 points on the NSAA total score). The futility analysis demonstrated that taldefgrobep alfa did not result in functional change for boys with DMD. The program was subsequently terminated in 2019. Overall, there were no safety concerns, and no patients were withdrawn from treatment as a result of treatment-related adverse events or serious adverse events. NCT02145234, NCT02515669, NCT03039686.

A High-Protein Diet Promotes Atrial Arrhythmogenesis via Absent-in-Melanoma 2 Inflammasome.

High-protein diets (HPDs) offer health benefits, such as weight management and improved metabolic profiles. The effects of HPD on cardiac arrhythmogenesis remain unclear. Atrial fibrillation (AF), the most common arrhythmia, is associated with inflammasome activation. The role of the Absent-in-Melanoma 2 (AIM2) inflammasome in AF pathogenesis remains unexplored. In this study, we discovered that HPD increased susceptibility to AF. To demonstrate the involvement of AIM2 signaling in the pathogenesis of HPD-induced AF, wildtype (WT) and Aim2-/- mice were fed normal-chow (NC) and HPD, respectively. Four weeks later, inflammasome activity was upregulated in the atria of WT-HPD mice, but not in the Aim2-/--HPD mice. The increased AF vulnerability in WT-HPD mice was associated with abnormal sarcoplasmic reticulum (SR) Ca2+-release events in atrial myocytes. HPD increased the cytoplasmic double-strand (ds) DNA level, causing AIM2 activation. Genetic inhibition of AIM2 in Aim2-/- mice reduced susceptibility to AF, cytoplasmic dsDNA level, mitochondrial ROS production, and abnormal SR Ca2+-release in atrial myocytes. These data suggest that HPD creates a substrate conducive to AF development by activating the AIM2-inflammasome, which is associated with mitochondrial oxidative stress along with proarrhythmic SR Ca2+-release. Our data imply that targeting the AIM2 inflammasome might constitute a novel anti-AF strategy in certain patient subpopulations.

Remdesivir: treatment of COVID-19 in special populations.

Remdesivir (RDV) is the mainstay antiviral therapy for moderate to severe COVID-19. Although remdesivir was the first drug approved for COVID-19, information about its efficacy and safety profile is limited in a significant segment of the population, such as people with underlying diseases, the elderly, children, and pregnant and lactating women. The efficacy and safety profile of RDV in disease progression, renal impairment, liver impairment, immunosuppression, geriatrics, pediatrics, pregnancy, and breastfeeding in COVID-19 patients was evaluated. The databases searched included Embase, Scopus, and PubMed. Only English language studies enrolling specific subpopulations with COVID-19 and treated with RDV were included. Thirty-nine clinical trials, cohorts, cross-sectional studies, and case series/reports were included. Most supported the benefits of RDV therapy for COVID-19 patients, such as lessening the duration of hospitalization, alleviating respiratory complications, and reducing mortality. Adverse effects of RDV, including liver and kidney impairment, were, for the most part, moderate to mild, supporting the safety profile of RDV therapy. RDV therapy was well tolerated, no new safety signals were detected, and liver function test abnormalities were the most common adverse events. Moreover, RDV, for the most part, was effective in managing the complications of COVID-19 and reducing mortality in these patients, except for patients with kidney impairment. Future studies, including RCTs, should include these subpopulations of patients to avoid delays associated with receiving proper medication through compassionate use programs.

Machine learning hypothesis-generation for patient stratification and target discovery in rare disease: our experience with Open Science in ALS.

Advances in machine learning (ML) methodologies, combined with multidisciplinary collaborations across biological and physical sciences, has the potential to propel drug discovery and development. Open Science fosters this collaboration by releasing datasets and methods into the public space; however, further education and widespread acceptance and adoption of Open Science approaches are necessary to tackle the plethora of known disease states. In addition to providing much needed insights into potential therapeutic protein targets, we also aim to demonstrate that small patient datasets have the potential to provide insights that usually require many samples (>5,000). There are many such datasets available and novel advancements in ML can provide valuable insights from these patient datasets. Using a public dataset made available by patient advocacy group AnswerALS and a multidisciplinary Open Science approach with a systems biology augmented ML technology, we aim to validate previously reported drug targets in ALS and provide novel insights about ALS subpopulations and potential drug targets using a unique combination of ML methods and graph theory. We use NetraAI to generate hypotheses about specific patient subpopulations, which were then refined and validated through a combination of ML techniques, systems biology methods, and expert input. We extracted 8 target classes, each comprising of several genes that shed light into ALS pathophysiology and represent new avenues for treatment. These target classes are broadly categorized as inflammation, epigenetic, heat shock, neuromuscular junction, autophagy, apoptosis, axonal transport, and excitotoxicity. These findings are not mutually exclusive, and instead represent a systematic view of ALS pathophysiology. Based on these findings, we suggest that simultaneous targeting of ALS has the potential to mitigate ALS progression, with the plausibility of maintaining and sustaining an improved quality of life (QoL) for ALS patients. Even further, we identified subpopulations based on disease onset. In the spirit of Open Science, this work aims to bridge the knowledge gap in ALS pathophysiology to aid in diagnostic, prognostic, and therapeutic strategies and pave the way for the development of personalized treatments tailored to the individual's needs.

Bumetanide to treat autism spectrum disorders: are complex administrative regulations fit to treat heterogeneous disorders?

Introduction: Extensive experimental observations suggest that the regulation of ion fluxes and, notably, chloride are impacted in autism spectrum disorders (ASD) and other neurodevelopmental disorders. The specific NKCC1 cotransporter inhibitor Bumetanide has been shown to attenuate electrophysiological and behavioral features of ASD in experimental models. Both pilot and phase 2 double-blind randomized independent trials have validated these effects with thousands of children treated successfully. Both brain imaging and eye tracking observations also validate these observations. However, final large phase 3 trials failed, with no significant differences between placebo and treated children. Methods: Here, I discuss the possible reasons for these failures and discuss the exclusive reliance on complex patent cooperation Treaty (PCT) regulations. Indeed, available data suggest that bumetanide responders could be identified by relying notably on EEG measures, suggesting that biological sub-populations of patients might benefit from the treatment. Results: These observations raise important debates on whether treating only a % of children with ASD is acceptable. Discussion: It is likely that in many disorders, the heterogeneity of the pathological event precludes a single general treatment for all, suggesting that trials centered on selective populations of responders might be essential for large clinical trials to succeed.

Effects of Reishimmune-S, a Fungal Immunomodulatory Peptide Supplement, on the Quality of Life and Circulating Natural Killer Cell Profiles of Patients With Early Breast Cancer Receiving Adjuvant Endocrine Therapy.

To evaluate the effects of Reishimmune-S, a fungal immunomodulatory peptide, on the quality of life (QoL) and natural killer (NK) cell subpopulations in patients receiving adjuvant endocrine therapy (ET) for breast cancer (BC). Patients who received adjuvant ET for stage I-III hormone receptor-positive BC without active infection were enrolled in this prospective pilot study. Reishimmune-S was administered sublingually daily for 6 months. QoL scores, circulating immune cell levels, including lymphocyte/NK cell subpopulations, and plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured at baseline and every 4 weeks. Data were analyzed using linear mixed-effect regression models. Nineteen participants were included in the analyses. One patient with underlying asthma did not complete the study owing to the occurrence of skin rashes 15 days after the initiation of Reishimmune-S. No other adverse events were reported. Reishimmune-S supplementation significantly improved the cognitive function at 3 months and significantly decreased the fatigue and insomnia levels at 3 and 6 months, respectively. There was no significant change in the global health/QoL score between baseline and week 4 of treatment. The proportion of CD19+ lymphocytes was significantly higher at 3 and 6 months, and that of NKG2A+ and NKp30+ NK cells was significantly lower at 6 months than at baseline. In addition, fatigue positively correlated with the proportion of NKp30+ NK cells (β ± standard error: 24.48 ± 8.75, P = .007 in the mixed-effect model). Short-term supplementation with Reishimmune-S affected the circulating immune cell composition and exerted positive effects on cognitive function, fatigue, and insomnia in patients with BC undergoing adjuvant ET, providing a potential approach for the management of treatment-related adverse reactions in this patient population.

Expansion of distinct peripheral blood myeloid cell subpopulations in patients with rheumatoid arthritis-associated interstitial lung disease

ObjectivesInterstitial lung disease (ILD) is associated with significant mortality in rheumatoid arthritis (RA) patients with key cellular players remaining largely unknown. This study aimed to characterize inflammatory and myeloid derived suppressor cell (MDSC) subpopulations in RA-ILD as compared to RA, idiopathic pulmonary fibrosis (IPF) without autoimmunity, and controls. MethodsPeripheral blood was collected from patients with RA, RA-ILD, IPF, and controls (N = 60, 15/cohort). Myeloid cell subpopulations were identified phenotypically by flow cytometry using the following markers:CD45,CD3,CD19,CD56,CD11b,HLA-DR,CD14,CD16, CD15,CD125,CD33. Functionality of subsets were identified with intracellular arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS) expression. ResultsThere was increased intermediate (CD14++CD16+) and nonclassical (CD14+/-CD16++) and decreased classical (CD14++CD16-) monocytes in RA, RA-ILD, and IPF vs. control. Intermediate monocytes were higher and classical monocytes were lower in RA-ILD vs. RA but not IPF. Monocytic (m)MDSCs were higher in RA-ILD vs. control and RA but not IPF. Granulocytic (g)MDSCs did not significantly differ. In contrast, neutrophils were increased in IPF and RA-ILD patients with elevated expression of Arg-1 sharing similar dimensional clustering pattern. Eosinophils were increased in RA-ILD vs. controls, RA and IPF. Across cohorts, iNOS was decreased in intermediate/nonclassical monocytes but increased in mMDSCs vs. classical monocytes. In RA-ILD, iNOS positive mMDSCs were increased versus classic monocytes. ConclusionsMyeloid cell subpopulations are significantly modulated in RA-ILD patients with expansion of CD16+ monocytes, mMDSCs, and neutrophils, a phenotypic profile more aligned with IPF than other RA patients. Eosinophil expansion was unique to RA-ILD, potentially facilitating disease pathogenesis and providing a future therapeutic target.

Sunitinib malate induces cell death in adult human cardiac progenitor cells

Sunitinib malate is known to cause cardiotoxicity in a sub-population of patients, with heart failure seen in more severe cases. Cardiac progenitor cells (CPCs) have been identified in adult human myocardium and contribute to overall tissue maintenance, with previous work identifying negative impacts of sunitinib on these cells. This study aimed to characterise the toxic effects of sunitinib in human CPCs, applying sunitinib concentrations equivalent to clinical plasma levels to these cells in vitro. Cell viability was reduced by 26.5 ± 6.6 % by 2 μM sunitinib for 24 h (p < 0.01); this concentration also induced fold-change increases in gene expression of: calpain (3.1 ± 0.73, p < 0.05), FAS (2.3 ± 0.8, p < 0.05) and BAX (1.9 ± 0.2, p < 0.05), and a decrease in BCL-2 (3.5 ± 0.0, p < 0.001), vs. control (1.0 ± 0.0). This was affirmed by sunitinib inducing fold changes in protein expression of: calpain-1 (2.5 ± 0.5, p < 0.05); FAS receptor (2.1 ± 0.2, p < 0.05) and BAX (2.1 ± 0.2, p < 0.05) vs. control (1.0 ± 0.0). These results indicated that sunitinib induced apoptosis in CPCs, but negative annexin V staining and lack of protection by caspase inhibitors indicated this was not the cell death pathway activated. Further investigation found sunitinib was concentrated in the lysosomes and autophagosomes within CPCs, but did not induce accumulation of acidic organelles. In conclusion, these data confirm that cell death is caused by sunitinib in CPCs at concentrations equivalent to clinical plasma levels, inducing cell death pathway signals that lead to non-apoptotic cell death.