Effects Of Drugs Research Articles

Drugs causing prostate-specific antigen changes: the food and drug administration adverse event reporting system combined with Mendelian randomization analysis

ABSTRACT Background Prostate cancer is one of the most common malignancies in men worldwide, and prostate-specific antigen (PSA) screening is widely used for its early detection. Drug use may affect PSA levels, but the effect for most drugs is currently unknown. Methods This study first investigated drugs related to PSA changes through the Food and Drug Administration Adverse Event Reporting System (FAERs) database, and then used a Mendelian randomization (MR) method to explore the causal relationship between specific drugs and PSA changes using a genome-wide association study (GWAS) data. The statistical analysis software SAS and R were used in the study. Results Through analysis of the FAERs database, 22 drugs were found to be associated with an increase in PSA, and 14 drugs were associated with a decrease in PSA. MR analysis showed that the use of tamsulosin may lead to an increase in PSA. Heterogeneity test, horizontal pleiotropy test and leave-one-out Analysis verified the stability of the results. MR analyses for other drugs did not show statistical significance. Conclusion This study provided a basis for better understanding the impact of medications on prostate health, helping to avoid overdiagnosis or underdiagnosis of high-risk patients. However, research still requires larger-scale validation and in-depth exploration.

Clinical trial design and treatment effects: a meta-analysis of randomised controlled and single-arm trials supporting 437 FDA approvals of cancer drugs and indications

ObjectivesThis study aims to analyse the association between clinical trial design and treatment effects for cancer drugs with US Food and Drug Administration (FDA) approval.DesignCross-sectional study and meta-analysis.SettingData from Drugs@FDA,...

Naturalistic psychedelic therapy: The role of relaxation and subjective drug effects in antidepressant response

Naturalistic psychedelic therapy: The role of relaxation and subjective drug effects in antidepressant response

Erratum: Assessing the credibility of a drug's effects: identification and judgment of uncertainty by the Dutch Medicines Evaluation Board

Erratum: Assessing the credibility of a drug's effects: identification and judgment of uncertainty by the Dutch Medicines Evaluation Board

A Novel 5-Chloro-N-Phenyl-1 H-Indole-2-carboxamide Derivative as a Glycogen Phosphorylase Inhibitor: Evaluating the Long-Term Drug Effects on Muscle Function for the First Time

Compound 1 was previously identified by our team as a glycogen phosphorylase (GP) inhibitor with glucose-lowering activity and demonstrated to have protective effects against myocardial and cerebral ischemia. However, its impact on muscle function has not been clarified. This study is the first to evaluate the long-term effects of GP inhibitors on muscle function and metabolism. After a 28-day administration of Compound 1, we performed assays to assess muscle function and biochemical parameters in rats. We observed reductions in peak holding force, duration, tetanic contraction force, single-contraction force, and electromyographic signals under 20 s and 10 min contraction stimuli. The metabolic analysis showed no significant effects on muscle glycogen, ATP, lactic acid, and uric acid levels at low doses. In contrast, medium to high doses resulted in increased glycogen, decreased ATP, and reduced lactic acid (only at high doses), without affecting uric acid. These findings suggest that Compound 1 may adversely affect muscle function in rats, potentially due to the glycogen inhibition effects of GP inhibitors. This study provides crucial safety data and insights into the long-term effects of GP inhibitors on rat muscles, which will guide future developments and applications.

Regional deep atrophy: Using temporal information to automatically identify regions associated with Alzheimer’s disease progression from longitudinal MRI

Abstract Longitudinal assessment of brain atrophy, particularly in the hippocampus, is a well-studied biomarker for neurodegenerative diseases, such as Alzheimer’s disease (AD). Estimating brain progression patterns can be applied to understanding the therapeutic effects of amyloid-clearing drugs in research and detecting the earliest sign of accelerated atrophy in clinical settings. However, most state-of-the-art measurements calculate changes directly by segmentation and/or deformable registration of MRI images, and may misreport head motion or MRI artifacts as neurodegeneration, impacting their accuracy. In our previous study, we developed a deep learning method DeepAtrophy that uses a convolutional neural network to quantify differences between longitudinal MRI scan pairs that are associated with time. DeepAtrophy has high accuracy in inferring temporal information from longitudinal MRI scans, such as temporal order or relative interscan interval. DeepAtrophy also provides an overall atrophy score that was shown to perform well as a potential biomarker of disease progression and treatment efficacy. However, DeepAtrophy is not interpretable, and it is unclear what changes in the MRI contribute to progression measurements. In this paper, we propose Regional Deep Atrophy (RDA), which combines the temporal inference approach from DeepAtrophy with a deformable registration neural network and attention mechanism that highlights regions in the MRI image where longitudinal changes are contributing to temporal inference. RDA has similar prediction accuracy as DeepAtrophy, but its additional interpretability makes it more acceptable for use in clinical settings, and may lead to more sensitive biomarkers for disease monitoring and progression understanding in preclinical AD.

Simultaneous Confidence Intervals for Signal Detection and Ascertaining Precision of Adverse Event Rates in Clinical Trials

The marketing authorization of a medicinal product is contingent upon demonstration of safety and efficacy in support of the product’s labeled conditions of use. To demonstrate safety, one group of adverse events that requires detailed consideration is common adverse reactions (ARs). ARs and their frequency are reported in prescription drug labeling in the US and EU. The determination of these adverse reactions generally takes a simple approach—usually, inclusion is through the frequency of reporting and whether the adverse event (AE) rate for the drug exceeds the placebo rate. This standard method does not account for confounders or multiplicity. To overcome these limitations, we propose a Monte Carlo approach to detect drug safety signals in clinical trials. We fit regression models incorporating covariates to assess the drug effect on the rate of AEs. Adjustment for multiplicity is carried out through the construction of simultaneous confidence intervals accounting for arbitrary correlations. A computationally efficient multiplier bootstrap approach using the Rademacher sequences is developed to generate random samples from the joint distribution of the estimators for all the AE rates. Compared to Bonferroni-based methods, the proposed method leads to narrower simultaneous confidence intervals and is more powerful in detecting potential safety signals.

The Effects of Diet, Dietary Supplements, Drugs and Exercise on Physical, Diagnostic Values of Urine Characteristics

Background/Objectives: This review summarizes the current knowledge about factors that affect the physical characteristics of urine. It highlights proper urine sample collection and displays factors like diet, hydration status, and medications that can alter urine color, odor, clarity, specific gravity and pH. Results: Urinalysis is a minimally invasive examination of a patient’s health, especially concerning nephrological and endocrinological abnormalities, as well as dietary habits and stimulants used. Certain deviations in appearance, composition or frequency/pain during urination may indicate an ongoing disease process in the body. Based on laboratory results, further medical treatment is determined. The reason for a change in the color of the urine, for its clouding or intense odor may be a disease, as well as the consumption of food, medication, intensive physical exercise or inadequate hydration of the body. Well-standardized procedures for collecting, transporting, preparing and analyzing samples should become the basis for an effective diagnostic strategy in urinalysis. It is worth noting that pharmacists in pharmaceutical care are often the first people to whom a patient turns for health advice and for the interpretation of simple laboratory tests. Acquiring the ability to interpret the results of laboratory tests and the principles of proper sampling for laboratory tests is indispensable in the process of possible counseling and providing reliable answers to patients’ questions. Conclusions: Although urinalysis is not recommended as a routine screening tool for the general population, it can prove to be a valuable source of patient health data in some cases as the data will be useful to physicians and pharmacists to more effectively diagnose and better care for patients.

Comparison of kidney and hepatic outcomes among sodium-glucose cotransporter-2 inhibitors: a retrospective study using multiple propensity scores

BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2i) have been reported to have effects beyond lowering blood glucose levels, with certain SGLT2i expanding their indications to chronic kidney disease and chronic heart failure. We focused on the hepatoprotective and renoprotective effects of six SGLT2i and assessed whether the effects were unique to each drug or common class effects, in addition to whether the renal and hepatoprotective effects vary based on renal and hepatic status.MethodsPatients with diabetes (ipragliflozin: 837, empagliflozin: 850, canagliflozin: 922, dapagliflozin: 590, tofogliflozin: 288, and luseogliflozin: 193) who initiated SGLT2i treatment and were monitored for one year were included. The propensity score (PS) was calculated using patient backgrounds (age, sex, height, weight, body mass index [BMI], disease duration, concomitant diabetes medications, underlying conditions, glycated hemoglobin [HbA1c], estimated glomerular filtration rate [eGFR], aspartate aminotransferase [AST], alanine aminotransferase [ALT], high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglyceride [TG] levels) as covariates. Additionally, the inverse probability of treatment weighting (IPTW) approach was used to compare liver and renal function test values.ResultsPre- and 12-month post-treatment comparisons demonstrated a significant reduction in hepatic function (AST and ALT) and an increase in renal function (eCcr and eGFR) for all SGLT2i. Comparison of differences between pre- and 12-month post-treatment using the IPTW approach demonstrated no significant differences in AST, ALT, and eGFR levels between SGLT2i. At 12 months post-treatment, 67 patients were classified as having a more severe CKD than those at pre-treatment, representing only 1.8% of all patients (67/3,680). Similarly, 107 patients with AST and 147 patients with ALT were classified as having progressed to a more severe grade than at pre-treatment, representing only 2.9 and 4.0%, respectively.ConclusionsRenoprotective and hepatoprotective effects are class effects of SGLT2i, and their effects are thought to be independent of kidney or liver status.

Preparation of injectable self-healing hydrogels using carboxymethyl chitosan and oxidized dextran with incorporating quercetin-loaded PF127 micelles for wound healing

Rapid achievement of the irregularly shaped post-wound closure is closely related to the effectiveness of clinical hydrogel-based wound dressings to inhibit microbial invasion and promote wound healing. Herein, an injectable and self-healing hydrogel with rapid gelation was engineered based on carboxymethyl chitosan (CMCS) and oxidized dextran (Odex). The hydrophobic drug, quercetin, with antioxidant and antibacterial effects, was loaded in the PF127 micelles with an encapsulation efficiency of 59.06 %, and then quercetin-loaded PF127 micelles were ingeniously incorporated into the hydrogels. The prepared composite hydrogels not only showed a stable and sustained release behavior of quercetin, but also possessed excellent antioxidant activities and antibacterial properties against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. Moreover, the composite hydrogels with microstructure (150–250 μm) also exhibited self-healing and injectable properties. In addition, the survival rates of NIH 3T3 cells when cultured with hydrogel extract were all over 80 %, illustrating the excellent biocompatibility of hydrogels. Therefore, our prepared multifunctional composite hydrogels showed a broad prospect as wound dressings for treating acute skin injuries.

An Unusual Application of Multifunctional Nanozyme Derived from COF: Augmenting Chemoimmunotherapy while Attenuating Cardiotoxicity

AbstractEnhancing therapeutic efficacy while reducing the adverse effects of drugs is crucial in cancer treatments. In this study, nitrogen‐doped carbon nanospheres are synthesized with variable enzymatic activities through the pyrolysis of a covalent organic framework (COF). These nanospheres show increased peroxidase (POD) and oxidase (OXD) activities in the tumor microenvironment, generating reactive oxygen species (ROS) that help eliminate tumor cells. Under normal conditions, they display catalase (CAT) and superoxide dismutase (SOD) activities, promoting antioxidative protection. Their porous structure and π–π/hydrophobic interactions allow for the loading of the chemotherapeutic agent doxorubicin (DOX). The nanospheres are then enveloped by tumor cell membranes, stabilizing the drug load and enabling targeted drug delivery with pH‐sensitive release. This targeted system induces ferroptosis in tumor cells and activates a strong anti‐tumor immune response, leading to enhanced immunotherapy for breast cancer and reduced tumor metastasis to the lungs. Importantly, the varied enzymatic activities of the nanomedicine system help mitigate the cardiotoxicity of DOX chemotherapy, improving cancer treatment while minimizing side effects. This approach introduces a nano‐enzyme drug system with distinctive activities and innovative preparation, setting a new standard for efficient, low‐toxicity cancer therapy.

Modeling serum M-protein response for early detection of biochemical relapse in myeloma patients treated with bortezomib, lenalidomide and dexamethasone.

Multiple myeloma (MM) treatment guidelines recommend waiting for formal progression criteria (FPC) to be met before proceeding to the next line of therapy. As predicting progression may allow early switching to next-line therapy while the disease burden is relatively low, we evaluated the predictive accuracy of a mathematical model to anticipate relapse 180 days before the FPC is met. A subset of 470/1143 patients from the IA16 dataset who were initially treated with VRd (Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone) in the CoMMpass study (NCT01454297) were randomly split 2:1 into training and testing sets. A model of M-protein dynamics was developed using the training set and used to predict relapse probability in patients in the testing set given their response histories up to 12 or more months of treatment. The predictive accuracy of this model and M-protein "velocity" were assessed via receiver operating characteristics (ROC) analysis. The final model was a two-population tumor growth inhibition model with additive drug effect and transit delay compartments for cell killing. The ROC area under the curve value of relapse prediction 180 days ahead of observed relapse by FPC was 0.828 using at least 360 days of response data, which was superior to the M-protein velocity ROC score of 0.706 under the same conditions. The model can predict future relapse from early M-protein responses and can be used in a future clinical trial to test whether early switching to second-line therapy results in better outcomes in MM.

Effect of non-steroidal anti-inflammatory drugs on the management of postoperative pain after cardiac surgery: a multicenter, randomized, controlled, double-blind trial (KETOPAIN Study)

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are recommended for the management of acute postoperative pain as part of a multimodal strategy to reduce opioid use, relieve pain, and reduce chronic pain in non-cardiac surgery. However, significant concerns arise in cardiac surgery due to the potential adverse effects of NSAID including increased bleeding and acute kidney injury (AKI). We hypothesized that NSAIDs are effective against pain and safe in the early postoperative period following cardiac surgery, taking contraindications into account.MethodsThe KETOPAIN trial is a prospective, double blind, 1:1 ratio, versus placebo multicentric trial, randomizing 238 patients scheduled for cardiac surgery. Written consent will be obtained for all participants. The inclusion criterion is patients more than 18 years old undergoing for elective cardiac surgery under cardiopulmonary bypass (CPB). Patients will be allocated to the intervention (ketoprofen) group (n = 119) or the control (placebo) group (n = 119). In the intervention group, in addition to the standard treatment, patients will receive NSAIDs (ketoprofen) at a dose of 100 mg each 12 h 48 h after. The control group, in addition to the standard treatment, will receive a placebo of NSAIDs every 12 h for 48 h after surgery. An intention-to-treat analysis will be performed. The primary endpoint will be the intensity of acute postoperative pain at rest at 24 h from the end of surgery. Pain will be assessed using the numerous rating scale. The secondary endpoints will be postoperative pain on coughing during chest physiotherapy, postoperative pain until day 7, the pain trajectory between day 3 and day 7, cumulative opioid consumption within 48 h after surgery, nausea and vomiting, the occurrence of postoperative pulmonary complications within the first 7 days after surgery, neuropathic pain at 3 months, and quality of life at 3 months.DiscussionNSAIDs function as non-selective, reversible inhibitors of the cyclooxygenase enzyme and play a role in a multimodal pain management approach. While there are recommendations supporting the use of NSAIDs in major non-cardiac surgery, recent guidelines do not favor their use in cardiac surgery. However, this is based on low-quality evidence. Major concerns regarding NSAID use in cardiac surgery patients are potential increase in postoperative bleeding or AKI. However, few studies support the possible use of NSAIDs without the risk of bleeding and/or AKI. Also, in a recent French survey, many anesthesiologists reported using NSAIDs in cardiac surgery. To date, no large randomized study has been conducted to evaluate the efficacy of NSAIDs in the management of postoperative pain in cardiac surgery. The expected outcome of this study is an improvement in the management of acute postoperative pain in cardiac surgery with a multimodal strategy including the use of NSAIDs.Trial registrationClinicalTrials.gov NCT06381063. Registered on April 24, 2024.

Effectiveness and risk of ARB and ACEi among different ethnic groups in England: A reference trial (ONTARGET) emulation analysis using UK Clinical Practice Research Datalink Aurum-linked data.

Guidelines by the National Institute for Health and Care Excellence recommend an angiotensin receptor blocker (ARB) rather than an angiotensin-converting enzyme inhibitor (ACEi) for the treatment of hypertension for people of African and Caribbean descent, due to an increased risk of angioedema associated with ACEi use observed in US trials. However, the effectiveness and risk of these drugs in Black populations in UK routine care is unknown. We applied a reference trial emulation approach to UK Clinical Practice Research Datalink Aurum data (linked with data from Hospital Episode Statistics and Office for National Statistics) to study the comparative effectiveness of ARB and ACEi in ethnic minority groups in England, after benchmarking results against the ONTARGET trial. Approximately 17,593 Black, 30,805 South Asian, and 524,623 White patients receiving a prescription for ARB/ACEi between 1 January 2001 and 31 July 2019 were included with a median follow-up of 5.2 years. The primary composite outcome was cardiovascular-related death, myocardial infarction, stroke, or hospitalisation for heart failure with individual components studied as secondary outcomes. Angioedema was a safety endpoint. We assessed outcomes using an inverse-probability-weighted Cox proportional hazards model for ARB versus ACEi with heterogeneity by ethnicity assessed on the relative and absolute scale. For the primary outcome, 27,327 (18.0%) events were recorded in the ARB group (event rate: 25% per 5.5 person-years) and 80,624 (19.1%) events (event rate: 26% per 5.5 person-years) in the ACEi group. We benchmarked results against ONTARGET and observed hazard ratio (HR) 0.96 (95% CI: 0.95, 0.98) for the primary outcome, with an absolute incidence rate difference (IRD)% of -1.01 (95% CI: -1.42, -0.60) per 5.5 person-years. We found no evidence of treatment effect heterogeneity by ethnicity for the primary outcome on the multiplicative (Pint = 0.422) or additive scale (Pint = 0.287). Results were consistent for most secondary outcomes. However, for cardiovascular-related death, which occurred in 37,554 (6.6%) people, there was strong evidence of heterogeneity on the multiplicative (Pint = 0.002) and additive scale (Pint < 0.001). Compared to ACEi, ARB were associated with more events in Black individuals (HR 1.20 (95% CI: 1.02, 1.40); IRD% 1.07 (95% CI: 0.10, 2.04); number-needed-to-harm (NNH): 93) and associated with fewer events in White individuals (HR 0.91 (95% CI: 0.88, 0.93); IRD% -0.87 (95% CI: -1.10, -0.63); number-needed-to-treat (NNT): 115), and no differences in South Asian individuals (HR 0.97 (95% CI: 0.86, 1.09); IRD% -0.17 (95% CI: -0.87, 0.53)). For angioedema, HR 0.56 (95% CI: 0.46, 0.67) with no heterogeneity for ARB versus ACEi on the multiplicative scale (Pint = 0.306). However, there was heterogeneity on the additive scale (Pint = 0.023). Absolute risks were higher in Black individuals (IRD% -0.49 (95% CI: -0.79, -0.18); NNT: 204) compared with White individuals (IRD% -0.06 (95% CI: -0.09, -0.03); NNT: 1667) and no difference among South Asian individuals (IRD% -0.05 (95% CI: -0.15, 0.05) for ARB versus ACEi. These results demonstrate variation in drug effects of ACEi and ARB for some outcomes by ethnicity and suggest the potential for adverse consequences from current UK guideline recommendations for ARB in preference to ACEi for Black individuals.

Foundational model aided automatic high-throughput drug screening using self-controlled cohort study.

Developing medicine from scratch to governmental authorization and detecting adverse drug reactions (ADR) have barely been economical, expeditious, and risk-averse investments. The availability of large-scale observational healthcare databases and the popularity of large language models offer an unparalleled opportunity to enable automatic high-throughput drug screening for both repurposing and pharmacovigilance. To demonstrate a general workflow for automatic high-throughput drug screening with the following advantages: (i) the association of various exposure on diseases can be estimated; (ii) both repurposing and pharmacovigilance are integrated; (iii) accurate exposure length for each prescription is parsed from clinical texts; (iv) intrinsic relationship between drugs and diseases are removed jointly by bioinformatic mapping and large language model - ChatGPT; (v) causal-wise interpretations for incidence rate contrasts are provided. Using a self-controlled cohort study design where subjects serve as their own control group, we tested the intention-to-treat association between medications on the incidence of diseases. Exposure length for each prescription is determined by parsing common dosages in English free text into a structured format. Exposure period starts from initial prescription to treatment discontinuation. A same exposure length preceding initial treatment is the control period. Clinical outcomes and categories are identified using existing phenotyping algorithms. Incident rate ratios (IRR) are tested using uniformly most powerful (UMP) unbiased tests. We assessed 3,444 medications on 276 diseases on 6,613,198 patients from the Clinical Practice Research Datalink (CPRD), an UK primary care electronic health records (EHR) spanning from 1987 to 2018. Due to the built-in selection bias of self-controlled cohort studies, ingredients-disease pairs confounded by deterministic medical relationships are removed by existing map from RxNorm and nonexistent maps by calling ChatGPT. A total of 16,901 drug-disease pairs reveals significant risk reduction, which can be considered as candidates for repurposing, while a total of 11,089 pairs showed significant risk increase, where drug safety might be of a concern instead. This work developed a data-driven, nonparametric, hypothesis generating, and automatic high-throughput workflow, which reveals the potential of natural language processing in pharmacoepidemiology. We demonstrate the paradigm to a large observational health dataset to help discover potential novel therapies and adverse drug effects. The framework of this study can be extended to other observational medical databases.

Potential Effect of Nonsteroidal Anti-Inflammatory Drugs on Certain Hormones in Females in Basrah City

Nonsteriodial anti-inflammatory drugs (NSAIDs) are commonly used by women to control pain associated with menstruation period. The main objective of this study is to determine whether use of NSAIDs has impact on the levels of certain hormones in females or not. A cross-sectional study was conducted between participant women who were taken one of the following NSAIDs including diclofenac, ibuprofein and mefenamic acid, for at least one year and more during menstruation and control women (did not take any medication). Levels of follicle stimulating hormone (FSH), Luteinizing hormone (LH), testosterone, prolactin and thyroid stimulating hormone (TSH) were measured by i-CHROMA method. The results showed that the level of LH significantly increased in groups of women who were taken NSAIDs during menstruation period, as well as diclofenac and mefenamic acid have a significant effect on the level of prolactin However, no clear changes were observed in the levels of FSH and testosterone at any type of NSAIDs that were used by the participant women in this study, the results were variable. No clear associations were observed between types of analgesic use and FSH, testosterone, prolactin and TSH. Further studies are required to confirm definite effect of NSAIDs on these hormones.

Olanzapine-induced Metabolic Syndrome and its Association with -759C&gt;T Polymorphism of the HTR2C Gene in Iraqi Schizophrenic Patients

The hazardous metabolic effects of treating schizophrenia patients with olanzapine comprise serotonin 2C receptor (5-HT2C) antagonists. Metabolic side effects of antipsychotic drugs, including lipid abnormalities, disturbed glucose metabolism, and weight gain, can have a major impact on treating psychiatric patients. The intent of this study was to investigate whether there is an associated link between the genetic polymorphism at -759C&gt;T in the promoter region of the 5-hydroxytryptamine 2C receptor (HTR2C) gene and the metabolic syndrome driven by olanzapine in schizophrenia patients. A cross-sectional study that involved fifty hospitalized patients with schizophrenia. The patients were split into two groups (metabolic and non-metabolic) according to the classification criteria of the metabolic syndrome. The HTR2C promoter region polymorphism was identified through sequencing using the Sanger method after polymerase chain reaction amplification of the extracted deoxyribonucleic acid. Even though none of the genotypes of the -759C&gt;T variant are associated with the propensity to develop metabolic syndrome, there is a significant difference in the -759C&gt;T variant's T allele (p-value = 0.001). The presence of the T allele in the -759 C/T variant was significantly associated with developing metabolic syndrome. Keywords: Schizophrenic patients, Olanzapine, Genetic polymorphism, 5-hydroxytryptamine 2C receptor (HTR2C) gene, -759C&gt;T.

Abstract A045: Disrupting local immunosuppression through combination myCAF/myeloid targeting in pancreatic cancer

Abstract Immunotherapy has revolutionized clinical care for many cancers, yet the approach has not been fully realized in immunologically cold tumors like Pancreatic Ductal Adenocarcinoma (PDAC). One striking hallmark of PDAC is local immunosuppression (LIS) which leads to cytotoxic T cell inactivation and exclusion. There is great need for an increased understanding of the cellular crosstalk within tumors and the identification of stromal and immune populations involved in shaping the tumor microenvironment (TME). Oncogenic KRAS activation in tumor cells promotes the invasion and proliferation of tumor-supporting stromal cells, while excluding cancer-targeted cytotoxic T cells. LIS is mediated by multiple subtypes of cancer-associated fibroblasts (CAFs) and myeloid cells resident within the tumor parenchyma. Multiple prior attempts to reverse LIS in PDAC by targeting individual stromal cell populations have been unsuccessful, alluding to the complexity of stromal crosstalk within the TME. The stromal diversity of PDAC complicates investigating paracrine cascades involving multiple cell types. To decipher diverse drug effects on altering the TME, we employ in vivo studies in mouse models recapitulating the human disease, as well as a novel tumor explant model that enables the short-term culture of intact human or murine PDAC. Importantly, PDAC explants maintain their histopathological architecture and cellular diversity over time. This medium-throughput platform allows for testing of multiple drugs and mechanistic hypotheses in the native PDAC TME. We show in preliminary data that Smoothened inhibition (SMOi) decreases proliferation and activity of myCAFs, but provokes the expansion of CD11b-positive myeloid cells in vivo. Thus, we hypothesize that LIS in PDAC is maintained by a delicate balance between myCAFs and myeloid cells, preventing effective T cell invasion. Single cell RNA-seq data comparing ctrl vs. SMOi-treated murine PDAC elucidates stromal subpopulations involved in the LIS phenotype and guides the identification of myeloid subtypes emerging after SMOi. Strikingly, we demonstrated that simultaneous SMOi and targeting myeloid cells via anti-Gr1 or CCR1 inhibition (CCR1i) significantly elevates cytotoxic T cell numbers up to 20x within the TME. We are currently investigating whether the activity of these T cells may be further potentiated through combination with immunomodulatory agents. By testing various treatment combination in the same TME, we will identify the best synergistic effects for future immunotherapy approaches in human PDAC. In summary, we are elucidating the complex mechanism behind LIS in PDAC by employing our novel explant culture system alongside in vivo studies. We aim to develop a translatable regimen to neutralize LIS, reactivating the cytotoxic T cells in the tumor periphery to invade, proliferate, and attack cancer cells. Citation Format: Marie C Hasselluhn, Lukas Vlahos, Dafydd Thomas, Quin T Waterbury, Alvaro Curiel Garcia, Amanda R Decker-Farrell, Tanner C Dalton, Stephen A Sastra, Carmine F Palermo, Timothy C Wang, Andrea Califano, Kenneth P Olive. Disrupting local immunosuppression through combination myCAF/myeloid targeting in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A045.

Combination of S-1 and the oral ATR inhibitor ceralasertib is effective against pancreatic cancer cells.

In our previous study, we found that the Chk1 inhibitor prexasertib enhances the antitumour effect of the oral anticancer drug S-1 against pancreatic cancer cells. In this study, we investigated the effect of combining S-1 and ceralasertib, an oral inhibitor of ATR, which is located upstream of Chk1. Ceralasertib is currently being investigated in multiple clinical trials for various cancers. The cell-proliferation inhibitory effect was measured by MTT assay, using the pancreatic cancer cell lines BxPC-3, SUIT-2, PANC-1, and MIA PaCa-2, while apoptosis was measured by flow cytometry using PI/Annexin staining. The mechanism underlying the combined effect was analysed using western blotting, and the antitumor effect was analysed using a mouse xenograft model. MTT assay revealed that the combination of S-1 and ceralasertib had a synergistic effect, leading to the suppression of cell proliferation. Measurement with PI/Annexin staining revealed that the combination of S-1 and ceralasertib induced apoptosis more efficiently than either drug alone. Western blotting results showed that ceralasertib inhibited S-1-induced activation of ATR and Chk1. The average estimated tumour volume after 3weeks of administration was 601 mm3 in the S-1 group, 580 mm3 in the ceralasertib group, and 298 mm3 in the combination group. The combination of S-1 and ceralasertib demonstrated a high antiproliferative effect in inhibiting tumour growth in vitro.

Engineering two-in-one DNA nanohybrids to evaluate anti-cancer effects through activatable RNA imaging

The development of DNA-based imaging techniques provides a promising way for theranostic applications. However, the dramatic chemical difference between DNA probes and therapeutics significantly hinders the construction of an ideal theranostic system for evaluation of therapeutic effects via in situ molecular imaging. In this work, we report a simple approach for the construction of a two-in-one DNA nanohybrid via one-step assembly of DNA probes and small molecular drugs, enabling evaluation of therapeutic effects via sensitive imaging of apoptosis-related mRNA. The nanohybrid was self-assembled from a rationally designed molecular beacon (MB) probe, doxorubicin (DOX, a chemotherapeutic drug) and Fe (II) ions through coordination interactions, which possesses anti-cancer effects from chemotherapeutics and the capability of efficient co-delivery of DNA probes without transfection agents. By tracking pro-apoptotic Bax mRNA expression with the MB, this system allows real-time monitoring of cell apoptotic process in response to drug treatment, enabling assessment of therapeutic effects of small molecular drugs. In addition, the approach is extended to the imaging of target microRNA in the drug treatment based on flexible DNA probe design, demonstrating the universality of this strategy. Moreover, the modular design of this DNA nanohybrid allows the introduction of photosensitizers into this system for efficient photodynamic therapy and simultaneous mRNA monitoring. This strategy expands the theranostic toolbox for the in situ evaluation of treatment response and screening anticancer drugs.