Triple Target Research Articles

Advancing care in type 2 diabetes and atherosclerosis: assessing pharmacist-led strategies in England's primary care - a retrospective observational study

Abstract Background Type 2 diabetes (T2D) mellitus is a complex multi-system disorder with a tendency to develop complications. ‘Persistence to therapy’ plans affect almost 50% of all people with T2D, leading to suboptimal glycaemic and cardiovascular (CVD) risk factor control. The interplay between T2D and established atherosclerotic cardiovascular disease (ASCVD) underscores the need for a comprehensive, multidisciplinary approach to care that addresses both glycaemic control and CVD risk factors. Purpose This study retrospectively analysed pharmacist-led interventions in patients living with T2D and established ASCVD in general practices in a large UK city. Methods A retrospective pre-post observational study was conducted using electronic health record data from men and women diagnosed with T2D and ASCVD. Participants attended an independent prescribing pharmacist-led clinic within 21 general practices. The practices operated linked and comprehensive electronic health records systems, facilitating access to high-quality longitudinal data that align with study objectives. Results A total of 380 patients received pharmacist-led interventions. Comparisons of pre-intervention and post-intervention data revealed a significant decrease in HbA1c levels (73.7 ± 10.7 mmol/mol vs 67.2 ± 8.5 mmol/mol, p < 0.01), systolic blood pressure (132 ± 10.2 mmHg vs 125.9 ± 9.9 mmHg, p < 0.01), and diastolic blood pressure (76.8 ± 5.9 mmHg vs 72.4 ± 5.0 mmHg, p < 0.001). Additionally, total cholesterol levels significantly reduced from 4.4 ± 0.7 mmol/L to 3.9 ± 0.7 mmol/L (p < 0.001). The proportion of patients achieving the triple target of HbA1c (≤58 mmol/mol), BP (≤140/80 mmHg), and total cholesterol (≤5 mmol/L) increased significantly from 2.4% before the intervention to 23.4% afterward (p < 0.001). The initiation of the sodium-glucose co-transporter 2 inhibitors (SGLT2i) therapies was the most common prescribing intervention (67%). Conclusions Pharmacist-led interventions in a general practice setting significantly improved several critical diabetes and CVD risk related outcomes. These findings underscore the potential benefits of integrating pharmacist-led care models into the management of T2D, particularly for patients with concurrent ASCVD and adopting an individualised, evidence-based approach to prescribing interventions.

Greatly isolated heterogeneous circulating tumor cells using hybrid engineered cell membrane-camouflaged magnetic nanoparticles

BackgroundCirculating tumor cells (CTCs) are considered as a useful biomarker for early cancer diagnosis, which play a crucial role in metastatic process. Unfortunately, the tumor heterogeneity and extremely rare occurrence rate of CTCs among billions of interfering leukocytes seriously hamper the sensitivity and purity of CTCs isolation.MethodsTo address these, we firstly used microfluidic chips to detect the broad-spectrum of triple target combination biomarkers in CTCs of 10 types of cancer patients, including EpCAM, EGFR and Her2. Then, we constructed hybrid engineered cell membrane-camouflaged magnetic nanoparticles (HE-CM-MNs) for efficient capture of heterogeneous CTCs with high-purity, which was enabled by inheriting the recognition ability of HE-CM for various CTCs and reducing homologous cell interaction with leukocytes. Compared with single E-CM-MNs, HE-CM-MNs showed a significant improvement in the capture efficiency for a cell mixture, with an efficiency of 90%. And the capture efficiency of HE-CM-MNs toward 12 subpopulations of tumor cells was ranged from 70 to 85%. Furthermore, by using HE-CM-MNs, we successfully isolated heterogeneous CTCs with high purity from clinical blood samples. Finally, the captured CTCs by HE-CM-MNs could be used for gene mutation analysis.ConclusionsThis study demonstrated the promising potential of HE-CM-MNs for heterogeneous CTCs detection and downstream analysis.Graphical abstract

Modeling of Integral Radiobiological Criteria for Simultaneous Irradiation of Multiple Targets with Different Absorbed Total Doses

Purpose: The paper is devoted to the comparison of simultaneous (SIB) and sequential (SEQ) radiation therapy of primary-multiple tumors with different absorbed total doses based on the modeling of integral radiobiological criteria. The research is aimed at optimization of treatment of rare primary-multiple tumors, development of optimal approaches based on the analysis of the effectiveness of different irradiation options. Material and methods: This research considers a system of primary-multiple targets, using a gynecologic tumor including vagina (adenosquamous carcinoma), endometrium (moderately differentiated adenocarcinoma with foci of squamous metaplasia), and lymph nodes as an example, to which certain equivalent total doses of irradiation must be delivered (EQD2>=74.8 Gy for vagina, EQD2>=85 Gy for endometrium). Different scenarios of two-stage and one-stage irradiation, including different combinations and doses for each target, are studied in the simulation. Results: Comparison of treatment plans for the triple target system shows that, performing sequential radiotherapy SEQ is characterized by higher levels of equivalent total dose delivered to the target volumes taking into account the total irradiation time and, consequently, to the critical organ volumes, especially in the rectum and sigmoid colon. In case of simultaneous irradiation SIB, the duration of treatment is five weeks instead of seven weeks, which reduces the value of the equivalent total dose to the target by 7-10 Gy. The value of the absorbed single dose delivered to the target volume is up to 3 Gy, which can be attributed to moderate hypofractionation. Levels of radiation exposure for critical organs in this case are much lower than when two-stage irradiation is used. Conclusion: Simultaneous integrated boost radiation therapy allows a significant reduction in radiation exposure to critical organs compared to sequential radiation therapy (reduction to single systems).

Socioeconomic inequalities in type 2 diabetes mellitus: a study based on a population-based survey in Iran

BackgroundType 2 diabetes mellitus (T2DM) is the most prevalent form of Diabetes Mellitus (DM), with social and economic determinants significantly influencing its prevalence. This study aimed to analyze the socioeconomic inequalities associated with T2DM in Iran.MethodsData from an observational survey in Iran, titled “Diabetes Care (DiaCare),” were utilized for this study. Socioeconomic inequalities were assessed through variables including Hemoglobin A1C (HbA1c), Fasting Blood Glucose (FBG), and Triple target (HbA1c, blood pressure, LDL-C), using concentration indices (CIs) and a multivariate logistic regression analysis. Individual socioeconomic status (SES) was determined by calculating an asset index using principle component analysis (PCA) based on their properties. Data analysis was conducted using STATA software version 14.ResultsA total of 13,321 participants were included in the study. The CIs were significantly positive for controlled HbA1c (0.0324) and triple target (0.1067), while for controlled FBG, it was 0.0125, although not significant. Among females, the CIs were significantly positive for controlled HbA1c (0.0745), FBG (0.0367), and triple target (0.209). Additionally, in the 45–55 and 65–75 age groups, the CIs were significantly positive for controlled HbA1c (0.0607) and FBG (0.0708), respectively. This index was significant for controlled Triple target in the 35–45 (0.376) and 65–75 (0.124) age groups. The CI for controlled FBG was significant in rural dwellers (-0.044) while the concentration of controlled triple target was significant in urban dwellers (0.0967). Controlled HbA1c showed significant concentration in both urban (0.0306) and rural (-0.0576) dwellers. Furthermore, the CIs were significant for controlled HbA1c in regions with medium prevalence (0.0534) and FBG in regions with low prevalence (-0.0277). This index was significantly positive for controlled triple target in regions with high prevalence (0.124).ConclusionsDiabetes care is more concentrated among individuals with higher SES. Policymakers should consider this to mitigate the inequality and alleviate the burden of T2DM.

Abstract 309: AHNAK nucleoprotein 2 tune oxidative stress and resistance to chemotherapy in triple negative breast cancer

Abstract Background: Resistance to chemotherapy is a major reason for the poorerprognosis in patients with triple negative breast cancer (TNBC). Growing evidence suggests that oxidative stress induced by reactive oxygen species (ROS) is an important factor in both tumourprogression and responses to chemotherapies, however, many signalling pathways and key molecular underlying the regulation of cancer cells to the ROS metabolism remains unclear. Aim: (i) To investigate the mechanistic role of AHNAK nucleoprotein 2 (AHNAK2) in TNBC and its links with breast cancer mortality, particularly caused by chemotherapeutic resistance; and (ii) to test a hypothesis that AHNAK2 facilitates the abnormal activation of ROSscavenging system, result in the resistance to chemotherapy in TNBC. Methods: The expression level of AHNAK2 was determined by immunohistochemical staining and analysed the mRNA expression profiles from The Cancer Genome Atlas of triple negative breast tumors. Roles of AHNAK2 in cancer cell growth, metastasis, chemotherapeutic resistanceand activation of oxygen scavenging systemwere determined by molecular and cell biology methods. A jetPEI nanocarrier was used as the vehicle for anti-AHNAK2 siRNAs in mouse models of cancer therapeutics. Results: AHNAK2 is a novel triple negative breast cancer target, which is overexpressed in TNBC tissues and significantly associated with clinical pathology of chemotherapeutic resistance and poor prognosis of tumour patients. Mechanistically, AHNAK2 antagonizes the ROS accumulation induced by epirubicinvia activating JAK-STAT signaling pathway and transportingphosphorylated STAT1 & STAT4 to the nucleus to promote the expression of SOD2, a key gene in ROS metabolism.And epirubicin enhanced AHNAK2 expression by induced the accumulation of ROS,which hence the Sp1-driven transcription of AHNAK2,result inde novo resistance. Furthermore, AHNAK2-specific siRNAs encapsulated by jetPEI nanocarriers prominently inhibit tumor growth and epirubicin-induced resistance in vivo. Conclusions: AHNAK2 plays a key role in resistance to chemotherapyby regulating the oxidative stressand ROS metabolism,representing a future biomarker and therapeutic target of TNBC. Citation Format: Na Hao. AHNAK nucleoprotein 2 tune oxidative stress and resistance to chemotherapy in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 309.

Analytical assessment of clinical sensitivity and specificities of pharmaceutical rapid SARS-CoV-2 detection nasopharyngeal swab testing kits in Pakistan.

Despite of the global unity against COVID-19 pandemic, the threat of SARS-CoV-2 variants on the lives of human being is still not over. SARS-CoV-2 pandemic has urged the need of rapid viral detection at earliest. To cope with gradually expanding scenario of SARS-CoV-2, accurate diagnosis is extremely crucial factor which should be noticed by international health organizations. Limited research followed by sporadic marketing of SARS-CoV-2 rapid pharmaceutical detection kits raises critical questions against quality assurance and quality control measures. Herein we aimed to interrogate effectivity and specificity analysis of SARS-CoV-2 pharmaceutical rapid detection kits (nasopharyngeal swab based) using conventional gold standard triple target real-time polymerase chain reaction (USFDA approved). A cross-sectional study was conducted over 1500 suspected SARS-CoV-2 patients. 100 real time-PCR confirmed patients were evaluated for pharmaceutical RDT kits based upon nasopharyngeal swab based kits. The SARS-CoV-2 nasopharyngeal swab based rapid diagnostic kit (NSP RDTs) analysis showed 78% reactivity. Among real time PCR confirmed negative subjects, 49.3% represented false positivity. The positive predictive analysis revealed 67.82%, while negative predictive values were 64.40%. The NSP RDTs showed limited sensitivities and specificities as compared to gold standard real time PCR. Valid and authentic detection of SARS-CoV-2 is deemed necessary for accurate COVID-19 surveillance across the globe. Current study highlights the potential consequences of inadequate detection of SARS-CoV-2 and emerging novel mutants, compromising vaccine preventable diseases. Current study emphasizes need to wake higher authorities including strategic organizations for designing adequate measures to prevent future SARS-CoV-2 epidemics.

A Novel PI3K γ/δ and DNA-PK Triple Inhibitor, BR101801, for r/r PTCL: A Phase 1a/b, Multi-Center, Open-Label Clinical Trial

Background BR101801, a triple inhibitor of PI3Kγ/δ and DNA-PK, inhibits not only the signal affecting cell growth caused by PI3Kγ/δ but also efficiently induces cell cycle arrest and apoptosis through inhibition of DNA-PK activation, with this triple target inhibition it decreases the stability of oncogenic protein, c-Myc (AACR2020 abstract #655). BR101801 is currently being evaluated in a phase 1a/b study in advanced hematologic malignancies. In phase 1a study, BR101801 exhibited evidence of clinical activity and was established at 200mg orally once daily 28-day cycle (RP2D) in patients with r/r PTCL (ASCO2023 abstract #7551). Methods This is a phase 1, open-label, multi-center, dose escalation (1a), and expansion (1b) study of BR101801 in adult patients with advanced hematologic malignancies (NCT04018248). In the phase 1a study, Dose was escalated at 50, 100, 200 and 325 mg QD. PTCL-NOS, AITL, FTCL and Nodal PTCL with TFH phenotype were determined as target indications for phase 1b with the RP2D. Results As of Jul 19, 2023, a total of 26 patients were enrolled in dose-escalation phase (n=12) and dose-expansion phase (n=14). The median age was 66 years (range of 30-83). Histological subtypes include PTCL-NOS (n=11, 42%), AITL (n=11, 42%), DLBCL (n=2, 8%), MZL (n=1, 4%) and MF (n=1, 4%). The majority of patients had stage III or IV (92%). In the phase 1a study, Dose limiting toxicity (DLT) occurred at 325 mg; thus, 200 mg QD was determined as the maximum tolerated dose (MTD) and RP2D. Of 19 evaluable patients with r/r PTCL (PTCL-NOS and AITL) in the phase 1 study. Patients' stage was III or IV (100%) with 47.4 % of patients having received three or more prior systemic therapies. The ORR was 31.6% (95% CI, 12.6-56.6) with 4 CRs (21.1%) and 2 PRs (10.5%), CBR was 47.4% (95% CI, 24.5-71.1). In median follow-up duration of 12.9 months, the median PFS was 7.5 months (95% CI, 1.7-NC), median OS and DoR (range of 1.9+-31.8+) has not reached. Currently, 5 patients still remain on treatment. Safety analysis was conducted for the 26 patients; 23 patients (88.5%) experienced adverse events (AEs). The most common (≥ 20%) AEs were Rash (23.1%), AST increased (23.1%), ALT increased (23.1%) and Cough (23.1%). Grade 3/4 ADRs occurred in 12 patients (46.2%) and those were (≥ 10%, frequency) AST increased (19.2%), ALT increased (15.4%), Neutropenia (15.4%). There were no treatment related mortality observed. Conclusion BR101801, the triple inhibitor of PI3K γ/δ and DNA-PK, demonstrated as a promising therapeutic option for r/r PTCLs patients. Preliminary results showed the ORR of 31.6% and a CR rate of 21.1%. Phase 2 study is warranted further investigate the safety and efficacy of BR101801 in r/r PTCL and Nodal TFH cell lymphoma at 200 mg QD orally.

Impact of a multicomponent integrated care delivery program on diabetes care goals achievement: a primary care quality improvement initiative

AimTo evaluate the impact of multicomponent integrated care (MIC) delivery program in a primary care real-life setting on diabetes care goals. MethodsPatients with T2D and usual primary care from the public health system in Mexico were invited to participate in a five-month ambulatory MIC quality initiative (DIAbetes Empowerment and Improvement of Care program, DIABEMPIC). Results841 patients who finished the program and with complete data were analyzed. The patients had a mean decrease in hemoglobin A1c, systolic and diastolic pressure, and LDL-cholesterol of 2.4%, 9 mmHg, 3 mmHg, and 22.5 mg/dL, respectively (p < 0.001). The achievement of the optimal triple target goal increased from 1.8% to 26.7% (p < 0.001). In the adjusted analysis, the diabetes knowledge and global self-care behavior score post-intervention, as well as the increment of global self-care behavior score were associated with the optimal composite risk factor control achievement. ConclusionThe incorporation of diabetes therapeutic education interventions to improve self-care behaviors along with adequate treatment intensification in diabetes care are fundamental to attaining optimal risk factor control and attenuating disease burden.

The chromatin- triple helix connection.

Mammalian genomes are extensively transcribed, producing a large number of coding and non-coding transcripts. A large fraction of the nuclear RNAs is physically associated with chromatin, functioning in gene activation and silencing, shaping higher-order genome organisation, such as involvement in long-range enhancer-promoter interactions, transcription hubs, heterochromatin, nuclear bodies and phase transitions. Different mechanisms allow the tethering of these chromatin-associated RNAs (caRNA) to chromosomes, including RNA binding proteins, the RNA polymerases and R-loops. In this review, we focus on the sequence-specific targeting of RNA to DNA by forming triple helical structures and describe its interplay with chromatin. It turns out that nucleosome positioning at triple helix target sites and the nucleosome itself are essential factors in determining the formation and stability of triple helices. The histone H3-tail plays a critical role in triple helix stabilisation, and the role of its epigenetic modifications in this process is discussed.

800-P: Predictors of HbA1c and dTIR Responses with iGlarLixi in Type 2 Diabetes—Patient-Level Exploratory Analyses of the LixiLan-L Trial

We aimed to evaluate derived Time in Range (dTIR) and identify predictors for achieving HbA1c and dTIR targets after commencing iGlarLixi in people with type 2 diabetes (T2D). These exploratory analyses of LixiLan-L, an open-label, randomized trial, included people with T2D advancing from basal insulin ± oral agents. dTIR (70−180 mg/dL), derived Time above Range (dTAR, &amp;gt;180 mg/dL), and derived Time below Range (dTBR, &amp;lt;70 mg/dL) were calculated from the 7-point SMBG profiles. HbA1c and dTIR were assessed at Week 30. Predictive factors for achieving targets were analyzed with univariable and multivariable stepwise logistic regression. Participants receiving iGlarLixi (n=366) showed an increase in dTIR from 64% at baseline (BL) to 82%, with 66% achieving dTIR ≥70% and 50% achieving clinically significant improvements (≥5% dTIR) at Week 30. The dTIR &amp;gt;70%, dTBR &amp;lt;4%, and dTAR &amp;lt;25% triple target was attained by 54% of participants receiving iGlarLixi. Weight change from BL, and lower HbA1c and total daily insulin dose at BL were predictors for attaining HbA1c &amp;lt;7.0%; lower BL HbA1c was a predictor of dTIR ≥70% (Table). In conclusion, iGlarLixi is associated with clinically significant HbA1c and dTIR improvements in T2D advancing from basal insulin. Lower BL HbA1c predicted achieving HbA1c &amp;lt;7.0% and dTIR ≥70% goals, whereas lower BL insulin dose predicted achieving HbA1c &amp;lt;7.0% only. Disclosure M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca. J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck &amp; Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck &amp; Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. A.Y.Cheng: Advisory Panel; Merck &amp; Co., Inc., Pfizer Inc., GlaxoSmithKline plc., Other Relationship; Diabetes Canada, Research Support; Applied Therapeutics Inc., Speaker's Bureau; Abbott, AstraZeneca, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., HLS Therapeutics Inc., Medtronic, Novo Nordisk, Sanofi, Insulet Corporation, Dexcom, Inc., Bausch Health, Canada. M.Al-sofiani: Consultant; Eli Lilly and Company, Speaker's Bureau; Sanofi, Medtronic, Vitalair. F.Lauand: Employee; Sanofi. L.Melas-melt: None. E.Souhami: Employee; Sanofi, Stock/Shareholder; Sanofi. J.Rosenstock: Advisory Panel; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Intarcia Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Research Support; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., Sanofi, Intarcia Therapeutics, Inc. Funding Sanofi

IGlarLixi provides a higher derived time-in-range versus insulin glargine 100 U/mL or lixisenatide in Asian Pacific people with type 2 diabetes: A post hoc analysis.

To evaluate the efficacy of iGlarLixi in Asian Pacific (AP) population with type 2 diabetes (T2D) using derived time-in-ranges calculated from seven-point self-measured blood glucose. Two phase III trials were analyzed. LixiLan-O-AP was performed in insulin-naive T2D patients (n=878) randomized to iGlarLixi, glargine 100 units/mL (iGlar), or lixisenatide (Lixi). LixiLan-L-CN was performed in insulin-treated T2D patients (n=426) randomized to iGlarLixi or iGlar. Changes in derived time-in-ranges from baseline to end-of-treatment (EOT) and estimated treatment differences (ETDs) were analyzed. The proportions of patients achieving ≥70% derived time-in-range (dTIR), ≥5% dTIR improvement, and the composite triple target (≥70% dTIR, <4% derived time-below-the-range [dTBR], and <25% derived time-above-the-range [dTAR]) were calculated. The changes from baseline to EOT in dTIR with iGlarLixi were greater versus iGlar (ETD1 : 11.45% [95% CI, 7.66 to 15.24]) or Lixi (ETD2 : 20.54% [95% CI, 15.74 to 25.33]) in LixiLan-O-AP, and versus iGlar (ETD: 16.59% [95% CI, 12.09 to 21.08]) in LixiLan-L-CN. In LixiLan-O-AP, the proportions of patients achieving ≥70% dTIR or ≥5% dTIR improvement at EOT with iGlarLixi were 77.5% and 77.8%, respectively, higher than with iGlar (61.1% and 75.3%) or Lixi (47.0% and 53.0%). In LixiLan-L-CN, the proportions of patients achieving ≥70% dTIR or ≥5% dTIR improvement at EOT were 71.4% and 59.8% with iGlarLixi, greater than with iGlar (45.4% and 39.5%). More patients achieved the triple target with iGlarLixi compared with iGlar or Lixi. iGlarLixi achieved greater improvements in dTIR parameters vs. iGlar or Lixi in insulin-naïve and insulin-experienced AP people with T2D. This article is protected by copyright. All rights reserved.

Achievement of the ABC goal among Canadians with type 2 diabetes and the influence of physical activity: data from the Canadian Health Measures Survey.

Achieving the three therapeutics targets known as ABC (A1c≤7.0%, LDL-C<2.0mmol/L, and resting BP<130/80mmHg), limiting sedentary behaviors as well as accumulating a total of 150 min/week of moderate-to-vigorous aerobic exercise reduce the risk of cardiovascular disease in type 2 diabetes (T2D) individuals. However, more recent data regarding the achievement of ABC over time in Canada is needed and it remains to be determined how sedentary behaviors and physical activity levels can influence its achievement. Analyses were performed using a total of 17582 individuals (18-79 years) from the 2007-2017 Canadian Health Measures Survey. Sedentary behaviors and physical activity levels were estimated using an accelerometer for a total of 7 consecutive days and quartiles of physical activity were used to categorize individuals. The prevalence of T2D has increased from 2007 to 2017 in the Canadian population (from 4.80% to 8.38%) with a considerable number of undiagnosed patients. The achievement of ABC went from 11.53% [11.49%-11.57%] in 2007 to 14.84% [14.80%-14.89%] in 2017 in T2D individuals. Moderate-to-vigorous physical activity (MVPA) levels were positively but weakly correlated to the achievement of the ABC (r=0.044; p=0.001), while sedentary time and light physical activity were not (r < -0.014; p=0.266). Only 8.8% of individuals with the lowest level of MVPA (Q1) reached the ABC while 15.1% of the most active individuals (Q4) reached the triple target. In addition to physical activity, other important factors such as body mass index and medication use should also be considered as modifiable contributing factors.

Triple targeting of mutant EGFRL858R/T790M, COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

We designed and synthesised novel quinazolinone tethered phenyl urea derivatives (6a–p) that triple target the double mutant EGFRL858R/T790M, COX-2, and 15-LOX. Compounds (6e, 6d, 6j, 6m, and 6n) not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFRL858R/T790M over wild-type EGFR. Except for 6e and 6n, all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o-treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads.

Turning down PI3K/AKT/mTOR signalling pathway by natural products: an in silico multi-target approach

ABSTRACT The PI3K/AKT/mTOR pathway is a significant target for cancer drug discovery. Many efforts have focused on discovering new inhibitors against key kinase proteins involved in this pathway for cancer treatment. PI3K/mTOR dual inhibitors, such as PKI-179, have been reported to be more effective than agents that act only on a single protein target. The present computational study aimed to discover triple target inhibitors against PI3K, AKT, and mTOR proteins. Accordingly, the PI3K protein bound with the ligand was used as input for e-pharmacophore modelling to generate the pharmacophore hypothesis and then screened for a library of 270,540 natural products from the Zinc database resulting in 57,220 compounds that matched the hypothesis. These compounds were then docked into the active site of PI3K, resulting in 292 compounds with better docking scores than the co-crystallized ligand. These compounds were re-docked into AKT and mTOR proteins. Besides, MM-GBSA binding free energy calculations, MD simulations, and ADMET prediction were carried out, leading to 5 potential triple-target inhibitors namely, ZINC000014644152, ZINC000014760695, ZINC000014644839, ZINC000095099451, and ZINC000005998557. In conclusion, these inhibitors may be possible leads for inhibiting PI3K/AKT/mTOR pathway, and they may be further evaluated in vitro and clinically as anticancer agents.

Could be FOXO3a, miR-96-5p and miR-182-5p useful for Brazilian women with luminal A and triple negative breast cancers prognosis and target therapy?

FOXO3a dysregulation is frequently implicated in tumorigenesis, and its inhibition can occur by several molecular mechanisms. Among these, post-transcriptional suppression by miRNAs has been associated with various cancers initiation. Here, we assessed the expression profiles of the most relevant miRNAs for breast tumorigenesis, using Luminal A (LA) and Triple-Negative (TN) breast cancer from Brazilian patients, by the quantitative real time-PCR method. Their potential prognostic role for the patients was also evaluated. We identified the miRNAs miR-96-5p and miR-182-5p, de-scribed as negative regulators of FOXO3A, with differential expression both in LA and TN tumors when compared to normal tissue. The miR-96-5p and miR-182-5p miRNAs were upregulated in LA (7.82 times, p < 0.005; 6.12 times, p < 0.005, respectively) and TN breast cancer samples (9.42 times, p < 0.0001; 8.51 times, p < 0.0001) compared to normal tissues. The samples with higher miR-96-5p and miR-182-5p expression (FR ≥ 4) were submitted for FOXO3a immunostaining. Reduced protein detection was observed in all of the tumors compared to normal tissues. The most prominent miRNA expression and FOXO3a protein suppression were observed in TN samples (p < 0.001), indicating the relevant role of these molecules in this tumor biology and clinical behavior. Our results corroborate the literature regarding to the relevance of FOXO3a in the breast cancer, and they open new perspectives for alternative target therapy options for Brazilian patients expressing both FOXO3a and its regulatory miRNAs.

Comparison of a Multiplex Real-Time PCR Technique with Oxford Nanopore Technologies Next-Generation Sequencing for Identification of SARS-CoV-2 Variants of Concern

Introduction: The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and their potential to endangering the global health has increased the demand for a fast-tracking method in comparison to the next-generation sequencing (NGS) as a gold standard assay, particularly in developing countries. This study was designed to evaluate the performance of a commercial multiplex real-time PCR technique (GA SARS-CoV-2 OneStep RT-PCR Kit, Iran) for identification of SARS-CoV-2 variants of concern (VOCs) compared to the Oxford Nanopore NGS assay. Methods: A total of 238 SARS-CoV-2-positive respiratory samples from different waves of COVID-19 in Iran were randomly selected in this study. To determine the SARS-CoV-2 VOC, the samples were analyzed via the commercial triple target assay, GA SARS-CoV-2 OneStep RT-PCR Kit, and NGS as well. Results: The results revealed good concordance between GA SARS-CoV-2 OneStep RT-PCR Kit and NGS for identification of SARS-CoV-2 VOCs. GA SARS-CoV-2 OneStep RT-PCR Kit identified Wuhan, Alpha, and Delta variants with 100% relative sensitivity and specificity. Regarding Omicron subvariants of BA.1, BA.2, and BA.4/5, the relative sensitivity of 100%, 100%, and 81.5% and the relative specificity of 95.3%, 93.5%, and 100% were observed. Conclusion: Overall, GA SARS-CoV-2 OneStep RT-PCR Kit can be used as a rapid and cost-effective alternative to NGS for identification of SARS-CoV-2 VOCs.

COVID-19 and the eye: Systemic and laboratory risk factors for retinopathy and detection of tear film SARS-CoV-2 RNA with a triplex RT-PCR assay.

To assess hospitalized COVID-19 inpatients for the prevalence of retinopathy and tear film SARS-CoV-2 RNA, and associated risk factors for their detection. Hospitalized COVID-19 patients underwent dilated ophthalmic examination and fundus photography. Conjunctival swabs were assessed for SARS-CoV-2 RT-PCR via a triple target assay. We assessed the relationships of retinopathy with clinical outcomes, systemic risk factors and laboratory data. The median age was 59.5 years and 29 (48%) were female. Retinopathy associated with COVID-19 was observed in 12 of 60 patients (20%). The median age of patients with COVID-19 retinopathy was 51.5 compared to 62.5 years in individuals without retinopathy (p = 0.01). Median BMI was 34.3 in patients with retinopathy versus 30.9 in those without retinopathy (p = 0.04). Fifteen of 60 patients (25%) tested SARS-CoV-2 RNA-positive in their tear film without a relationship with timing of illness and hospitalization. The N2 gene was particularly sensitive with 18 of 19 eyes (94.7%) showing N2-positivity, including 2 patients with alpha variant-positivity (B.1.1.7). Retinopathy was observed in 20% of patients hospitalized for COVID-19. Patients with retinopathy were more likely to be younger and have higher BMI than hospitalized patients without retinopathy. Tear film SARS-CoV-2 RNA was detected in 25% of patients. The relationship of obesity and age with retinopathy requires further investigation.

Management goal achievements of diabetes care in Iran: study profile and main findings of DiaCare survey.

This paper presented the methodology and main findings of a population-based survey to determine diabetes care status among type 2 diabetic subjects in Iran. The current study assessed treatment goal achievements in type 2 diabetics, diabetes care service utilization, prevalence of diabetes complications, and psychological effects of diabetes in a representative sample of Iranian population in urban and rural areas. This nationwide study was conducted between 2018 and 2020 as the observational survey entitled "Diabetes Care (DiaCare)". We studied a representative sample of participants with type 2 diabetes, aged 35-75years, living in urban and rural areas in all thirty- one provinces of Iran. Data were collected by an interviewer in a form of a questionnaire that includes demographic and socioeconomic status, family and drug history, lifestyle, and self-reported psychological status according to a Patient's Health Questionnaire (PHQ). Management goal achievements, diabetes care service utilization, diabetes complications and psychological effects of diabetes were also assessed. Physical measurements were measured based on standard protocol. Fasting blood glucose (FBG), HbA1c, lipid profile, and also urine albumin to creatinine ratio were obtained from all participants of the study. Overall, 13,334 people with type 2 diabetes in 31 provinces of Iran completed the survey (response rate: 99.6%). In total 13,321 participants, 6683(50.17%) women and 6638(49.83%) men were included in our analysis. Thirteen recruited patients refused after the consenting process and did not respond. The mean age (SD) of total participants was 54.86 ± 9.44years and 71.50% were from the urban areas. 13.66% of diabetic patients had achieved the triple target of management [controlled HbA1c, blood pressure, and Low-Density Lipoprotein-Cholesterol (LDL-C)] in the whole country. While 28.74% of people had controlled HbA1c and 33.40% of them had controlled FBG. Diabetic subjects living in rural areas had less controlled HbA1c (23.93 vs. 29.48), controlled FBG (29.50 vs. 34.20) and controlled triple targets (10.45 vs. 14.32) than those living in urban areas. Diabetic neuropathy and diabetic foot were more common in women than men, while end-stage of renal disease (ESRD) was more common in men than women. This population-based study provided representative information about diabetes care in Iran. The high prevalence of diabetes and low proportion of diabetes control in Iran implies that it is necessary to identify factors associated with poor treatment goal achievements. Besides, general improvements in management and care of diabetes are mandatory.

Abstract 5623: CD137 humanized mice for preclinical efficacy evaluation of therapeutic antibodies

Abstract CD137 (41-BB, tumor necrosis factor receptor superfamily 9), expressed on activated T cells and NK cells, has gained increased attention as an anti-tumor target because of remarkable clinical efficacy using either a single agent or in combination with other immune checkpoint inhibitors. We constructed CD137 humanized mice based on two different backgrounds, C57BL6 and BALB/c mice, as well as dual-target and triple-target mice crossbred with PD1/PDL1 humanized mice to create an ideal model to study CD137 target drugs. The normal immune cell population in peripheral blood were not affected in CD137 humanized mice, and hCD137 was expressed on T cells after the stimulation with a anti CD3 antibody. We verified the efficacy of anti-CD137 drugs in BALB/c-hCD137 mice inoculated with different cancer cell lines (i.e. CT26, EMT6 and 4T1). The drug Urelumab showed a dramatic response in the hCD137 mice model inoculated with CT26 and EMT6 but not with 4T1 cell line. In a rechallenge study, no tumors grew in tumor-free mice previously treated with Urelumab, with effector memory T cells increased in peripheral blood, indicating Urelumab has a relatively long-lasting anti-tumor effect. The combination of Urelumab and anti-PD1 has a stronger tumor growth inhibition effect than that of anti-CD137 or anti-PD1 monotherapy on dual-target or triple target mice. These data show that the humanized CD137 mouse is a suitable model for evaluating the monotherapies or combination therapies targeting CD137. Citation Format: Yunlong Jiang, Tingting Gu, Weiwei Yu, Hongyan Sun, Mingkun Zhang, Juan Liang, Shuai Li, Cunxiang Ju, Jing Zhao, Xiang Gao, Mark W. Moore. CD137 humanized mice for preclinical efficacy evaluation of therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5623.

Radiomodulation in Mixed, Complex Cancer Pain by Triple Target Irradiation in the Brain: A Preliminary Experience.

IntroductionUp to 30% of terminally ill cancer patients experiencing intense pain might be refractory to opioid treatment. Complex cancer pain can be a mixture of somatic, visceral, and neuropathic pain with few or no effective alternatives to ameliorate pain. Radiosurgery to treat refractory pain in cancer has been reported with different degrees of success. Radiomodulation in pain could be defined as a fast (<72 h), substantial (>50%) pain relief by focal irradiation to a peripheric, and/or central mediated pain circuitry. Based on our previous experience, mixed, refractory cancer pain is usually unresponsive to single target irradiation of the hypophysis. We treated three patients using a multi-target approach.MethodsThree terminally ill oncological patients experiencing refractory, complex, mixed pain from bone, abdomen, thorax, and brachial plexus were treated with triple target irradiation which consisted of irradiating with a maximum dose (Dmax) of 90 Gy to the hypophysis using either an 8 mm collimator with gamma ray (Infini) (Shenzhen, China: Masep Medical Company) or a 7.5 circular collimator with Cyberknife (Sunnyvale, CA: Accuray Inc.), the other two targets were the mesial structures of the thalamus bilaterally using a 4 mm collimator with Infini and the 5 mm circular collimator with CK delivering 90 Gy Dmax to each region. Patients had a VAS of 10 despite the best medical treatment.A correlation was made between the 45 Gy and 20 Gy isodose curves of the two different technologies to the Morel stereotactic atlas of the thalamus and basal ganglia for further understanding of dose distribution reconstructions in accordance with the São Paulo-Würzburg atlas of the Human Brain Project were performed. Lastly, a scoping review of the literature regarding radiosurgery for oncological pain was performed.ResultsRadiomodulation effect was achieved in all patients; case 1 had a VAS of five at 72 h, three at 15 days, and three at the time of death (21 days after treatment). Case 2 had a VAS of six at 72 h, five at 15 days, and four at the time of death (29 days after treatment). Case 3 had a VAS of five at 72 h, six at 15 days, and six at the time of death (30 days). Morphine rescues for cases 1 and 2 were reduced to 84%, and 70% for case 3. Overall, there were no adverse effects to treatment although excessive sleepiness was reported by one patient. After reading the title and abstract, only 14 studies remained eligible for full-text evaluation, and only nine studies met inclusion criteria after full-text reading. For most reports (seven), the target was the hypophysis and in two reports, the target was the thalamus either with single or bilateral irradiation.ConclusionsIn complex, for refractory oncological pain of mixed nature (nociceptive, neuropathic, and visceral), very few, if any, treatment alternatives are currently available. We provide a small proof of concept that multitarget intracranial radiosurgery might be effective in ameliorating pain in this population. The doses administered per target are the lowest that have shown effectiveness thus far, a different strategy might be needed as opposed to single target “large” dose approach that has been tried in the past for complex mixed refractory oncological pain. By no means, in our experience, these treatments traduce in elimination of pain, clinical results might make pain to be more bearable and respond better to pain medication.