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Benzodiazepines are frequently prescribed during pregnancy; however, evidence about possible teratogenicity is equivocal. We aimed to evaluate the association between first-trimester benzodiazepine use and the risk of major congenital malformations. Using Korea's nationwide healthcare database, we conducted a population-based cohort study of women who gave birth during 2011 to 2018 and their live-born infants. The exposure was defined as one or more benzodiazepine prescriptions during the first trimester. We determined the relative risks (RRs) and confidence intervals (CIs) of overall congenital malformations and 12 types of organ-specific malformations. Infants were followed from birth to death or 31 December 2019, whichever came first (up to 8 years of age). Propensity score fine stratification was employed to control for 45 potential confounders. Among a total of 3,094,227 pregnancies, 40,846 (1.3%) were exposed to benzodiazepines during the first trimester (mean [SD] age, 32.4 [4.1] years). The absolute risk of overall malformations was 65.3 per 1,000 pregnancies exposed to benzodiazepines versus 51.4 per 1,000 unexposed pregnancies. The adjusted RR was 1.09 (95% CI 1.05 to 1.13, p < 0.001) for overall malformations and 1.15 (1.10 to 1.21, p < 0.001) for heart defects. Based on mean daily lorazepam-equivalent doses, the adjusted RRs for overall malformations and heart defects were 1.05 (0.99 to 1.12, p = 0.077) and 1.12 (1.04 to 1.21, p = 0.004) for <1 mg/day and 1.26 (1.17 to 1.36, p < 0.001) and 1.31 (1.19 to 1.45, p < 0.001) for >2.5 mg/day doses, respectively, suggesting a dose-response relationship. A small but significant increase in risk for overall and heart defects was detected with several specific agents (range of adjusted RRs: 1.08 to 2.43). The findings were robust across all sensitivity analyses, and negative control analyses revealed a null association. Study limitations include possible exposure misclassification, residual confounding, and restriction to live births. In this large nationwide cohort study, we found that first-trimester benzodiazepine exposure was associated with a small increased risk of overall malformations and heart defects, particularly at the higher daily dose. The absolute risks and population attributable fractions were modest. The benefits of benzodiazepines for their major indications must be considered despite the potential risks; if their use is necessary, the lowest effective dosage should be prescribed to minimize the risk. ClinicalTrials.gov NCT04856436.

The development of chemoresistance is a major challenge in the treatment of several types of cancers in clinical settings. Stemness and chemoresistance are the chief causes of poor clinical outcomes. In this context, we hypothesized that understanding the signaling pathways responsible for chemoresistance in cancers is crucial for the development of novel targeted therapies to overcome drug resistance. Among the aberrantly activated pathways, the PI3K-Akt/Wnt/β-catenin signaling pathway is clinically implicated in malignancies such as colorectal cancer (CRC) and glioblastoma multiforme (GBM). Aberrant dysregulation of phospholipase D (PLD) has been implicated in several malignancies, and oncogenic activation of this pathway facilitates tumor proliferation, stemness, and chemoresistance. Crosstalk involving the PLD and Wnt/β-catenin pathways promotes the progression of CRC and GBM and reduces the sensitivity of cancer cells to standard therapies. Notably, both pathways are tightly regulated and connected at multiple levels by upstream and downstream effectors. Thus, gaining deeper insights into the interactions between these pathways would help researchers discover unique therapeutic targets for the management of drug-resistant cancers. Here, we review the molecular mechanisms by which PLD signaling stimulates stemness and chemoresistance in CRC and GBM. Thus, the current review aims to address the importance of PLD as a central player coordinating cross-talk between the PI3K/Akt and Wnt/β-catenin pathways and proposes the possibility of targeting these pathways to improve cancer therapy and overcome drug resistance. PLD Signaling in Cancer: Unveiling Pathways to Overcome Chemoresistance Cancer coming back after it seemed to have gone away is a big problem in treating cancers like colorectal cancer and a brain cancer called glioblastoma multiforme. This research looks at the part played by cancer stem cells (CSCs - cells within a tumor that can self-renew and cause the cancer to grow and come back) in cancer coming back and not responding to treatment. The scientists found that a pathway in the cells, called the Wnt/β-catenin signaling pathway, is important for keeping CSCs going. They also found that an enzyme (a type of protein that speeds up reactions in the body) called phospholipase D1 (PLD1) helps control this pathway. By stopping PLD1, they could lower the ability of CSCs to keep renewing themselves and make them more responsive to chemotherapy. This means that focusing on PLD1 could be a new way to treat cancers that don’t respond to existing treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Abstract Objective To evaluate the association between human papillomavirus (HPV) vaccination and serious adverse events in adolescent girls in South Korea. Design Cohort study. Setting A large linked database created by linking the Korea Immunization Registry Information System and the National Health Information Database, between January 2017 and December 2019. Participants 441 399 girls aged 11-14 years who had been vaccinated in 2017: 382 020 had been vaccinated against HPV and 59 379 had not been vaccinated against HPV. Main outcome measures Outcomes were 33 serious adverse events, including endocrine, gastrointestinal, cardiovascular, musculoskeletal, haematological, dermatological, and neurological diseases. A cohort design was used for the primary analysis and a self-controlled risk interval design for the secondary analysis; both analyses used a risk period of one year after HPV vaccination for each outcome. Incidence rate and adjusted rate ratios were estimated using Poisson regression in the primary analysis, comparing the HPV vaccinated group with the HPV unvaccinated group, and adjusted relative risks were estimated using conditional logistic regression in the secondary analysis. Results Among the 33 predefined serious adverse events, no associations were found with HPV vaccination in the cohort analysis, including Hashimoto’s thyroiditis (incidence rate per 100 000 person years: 52.7 v 36.3 for the vaccinated and unvaccinated groups; adjusted rate ratio 1.24, 95% confidence interval 0.78 to 1.94) and rheumatoid arthritis (incidence rate per 100 000 person years: 168.1 v 145.4 for the vaccinated and unvaccinated groups; 0.99, 0.79 to 1.25), with the exception of an increased risk observed for migraine (incidence rate per 100 000 person years: 1235.0 v 920.9 for the vaccinated and unvaccinated groups; 1.11, 1.02 to 1.22). Secondary analysis using self-controlled risk intervals confirmed no associations between HPV vaccination and serious adverse events, including migraine (adjusted relative risk 0.67, 95% confidence interval 0.58 to 0.78). Results were robust to varying follow-up periods and for vaccine subtypes. Conclusions In this nationwide cohort study, with more than 500 000 doses of HPV vaccines, no evidence was found to support an association between HPV vaccination and serious adverse events using both cohort analysis and self-controlled risk interval analysis. Inconsistent findings for migraine should be interpreted with caution considering its pathophysiology and the population of interest.

The tumor microenvironment (TME) is a complex ecosystem composed of not only malignant cells but also diverse stromal and immune cell populations that collectively shape tumor behavior. Metabolism is a central regulator of the TME, orchestrating intercellular communication through altered nutrients and signaling pathways to influence both the metabolic plasticity of cancer cells and functional balance of immune populations, ultimately determining tumor progression and antitumor immunity. Although tumor-intrinsic metabolic programs have been extensively characterized, emerging evidence highlights stromal metabolism as the dominant force sculpting immune responses within the TME. Among the nonmalignant stromal constituents, cancer-associated fibroblasts and cancer-associated adipocytes have emerged as metabolically active hubs that release and redistribute key metabolites, such as lactate, fatty acids and amino acids, to modulate the activity of both tumor and immune cells. Here we integrate recent advances in the understanding of stromal–immune metabolic crosstalk and elucidates how diverse metabolic mechanisms, including nutrient competition, mitochondrial remodeling, redox imbalance and immunometabolic rewiring, collectively reinforce an immunosuppressive TME and drive therapeutic resistance. Our study highlights the emerging strategies for selectively reprogramming these metabolic networks as potential therapeutic avenues. Deciphering these multilayered interactions will establish a conceptual and mechanistic foundation for reprogramming TME, restoring immune competence and enhancing the efficacy of current immunotherapies through metabolism-targeted interventions. stromal metabolism shapes tumor immunity and progression Cancer is not just a disease of cancerous cells but involves a complex environment around the tumor. This environment includes various cells and structures that interact with cancer cells, affecting how the cancer grows and responds to treatment. The study addresses how this environment, particularly cancer-associated fibroblasts (CAFs) and adipocytes (CAAs), influences cancer progression. Researchers found that CAFs and CAAs are not just passive structures but actively change their metabolism to support cancer growth. They conducted a review of existing studies to understand these interactions better. CAFs often increase glycolysis and produce lactate, which helps cancer cells grow. CAAs release fatty acids that fuel cancer cells and suppress immune responses. The study concludes that targeting these metabolic changes in CAFs and CAAs could improve cancer treatments by restoring immune function and reducing tumor growth. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Tumor cells shape the immunosuppressive tumor microenvironment (TME) through coordinated interactions with tumor-associated macrophages (TAMs), regulatory T cells (T regs ), immune checkpoint pathways and suppressive cytokines, thereby limiting the efficacy of immunotherapy across diverse cancer types. Phospholipase D (PLD) enzymes, particularly the PLD1 and PLD2 isoforms, have been implicated in oncogenic signaling and tumor progression; however, their tumor-intrinsic roles in modulating the immune landscape remain largely undefined. Here we demonstrated that both genetic ablation and pharmacological inhibition of PLD1 and PLD2 reprogram the TME and enhance antitumor immunity in a syngeneic melanoma model. Elevated PLD expression is associated with increased infiltration of M2-like TAMs, decreased ‘eat me’ signals and enhanced ‘don’t eat me’ signals. Conversely, loss or inhibition of PLD1 and PLD2 reduced T reg recruitment and enhanced infiltration of Th1, Th17 and cytotoxic CD8⁺ T cells, accompanied by downregulation of immune checkpoint molecules and restoration of T cell effector function. Depletion studies revealed that PLD-driven TAM polarization critically impairs CD8⁺ T cell-mediated antitumor responses. Mechanistically, PLD1 and PLD2 enhance CCL19 secretion, promote macrophage polarization toward an immunosuppressive phenotype and induce programmed death-ligand 1 (PD-L1) expression by activating the PI3K–Akt–NF-κB signaling axis, thereby promoting tumor immune evasion. Notably, PLD inhibition reduced CCL19 production, abrogated IFN-γ- or CCL19-induced PD-L1 expression, decreased TAM infiltration and increased CD8⁺ T cell infiltration, collectively shifting the TME toward an immune-activated state. These findings suggest that tumor-intrinsic PLD1 and PLD2 function as modulators of immune suppression and that PLD inhibition represents a promising strategy to overcome resistance to cancer immunotherapy. Targeting PLD enzymes boosts antitumor immunity in melanoma This study explores the role of phospholipase D (PLD) isoforms, PLD1 and PLD2, in melanoma, focusing on their impact on the tumor microenvironment (TME). The authors reveal that PLD1/2 are upregulated in melanoma, promoting tumor growth and immune evasion by modulating macrophage polarization and PD-L1 expression. Using CRISPR–Cas9 knockout models and pharmacological inhibition, they demonstrate that PLD1/2 deficiency shifts macrophages from an M2-like to an M1-like phenotype, enhancing T cell-mediated antitumor immunity. PLD1/2 deficiency reduces secretion of CCL19, which functions as an upstream regulator of immunosuppressive macrophage polarization and PD-L1 expression via the PI3K–Akt–NF-κB pathway. The findings suggest that targeting PLD1/2 could enhance cancer immunotherapy by reprogramming the immune landscape, highlighting the potential of PLD inhibitors as therapeutic agents. Future research could explore the applicability of these findings across different cancer types and further elucidate the signaling pathways involved. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Phospholipase D (PLD) is a potential therapeutic target against cancer. However, the contribution of PLD inhibition to the antitumor response remains unknown. We developed a potent and selective PLD1 inhibitor based on computer-aided drug design. The inhibitor enhanced apoptosis in colorectal cancer (CRC) cells but not in normal colonic cells, and in vitro cardiotoxicity was not observed. The inhibitor downregulated the Wnt/β-catenin signaling pathway and reduced the migration, invasion, and self-renewal capacity of CRC cells. In cancer, therapeutic engagement of immunogenic cell death (ICD) leads to more effective responses by eliciting the antitumor immunity of T cells. The CRC cells treated with the inhibitor showed hallmarks of ICD, including downregulation of “do not eat-me” signals (CD24, CD47, programmed cell death ligand 1 [PD-L1]), upregulation of “eat-me” signal (calreticulin), release of high-mobility group Box 1, and ATP. PLD1 inhibition subsequently enhanced the phagocytosis of cancer cells by macrophages through the surface expression of costimulatory molecules; as a result, the cancer cells were more susceptible to cytotoxic T-cell-mediated killing. Moreover, PLD1 inhibition attenuated colitis-associated CRC and orthotopically injected tumors, probably by controlling multiple pathways, including Wnt signaling, phagocytosis checkpoints, and immune signaling. Furthermore, combination therapy with a PLD1 inhibitor and an anti-PD-L1 antibody further enhanced tumor regression via immune activation in the tumor environment. Collectively, in this study, PLD1 was identified as a critical regulator of the tumor microenvironment in colorectal cancer, suggesting the potential of PLD1 inhibitors for cancer immunotherapy based on ICD and immune activation. PLD1 inhibitors may act as promising immune modulators in antitumor treatment via ICD. Colorectal cancer: Enzyme inhibition enhances immunotherapy A novel drug that can inhibit an enzyme involved in colorectal cancer progression shows promise in trials on mouse models. The phospholipase D1 (PLD1) enzyme reinforces a critical signaling pathway that promotes cancer progression and drug resistance. Using computer-aided drug design, South Korean researchers led by Do Sik Min and Gyoonhee Han at Yonsei University in Incheon and Seoul, respectively, have developed a drug that specifically binds to and inhibits PLD1. In trials, the researchers observed downregulation of PLD1’s associated signaling pathway, and reductions in the ability of colorectal cancer cells to migrate, invade and replicate. The drug suppressed the cancer cells’ “don’t-eat-me” signals and upregulated “eat-me” signals, triggering improved responses from the immune system. The drug was even more effective when used in combination with an immunotherapy agent.

Phospholipase D6 (PLD6) is a critical enzyme involved in mitochondrial fusion with a key role in spermatogenesis. However, the role of PLD6 in cancer remains unknown. Notably, Wnt signaling, energy metabolism and mitochondrial function show complex interactions in colorectal cancer (CRC) progression. Here we found that PLD6 is highly expressed in CRC and positively correlated with poor prognosis. We present a novel function of PLD6 in activating Wnt/β-catenin signaling by enhancing mitochondrial metabolism. PLD6 depletion suppresses the oncogenic properties of CRC cells and impairs mitochondrial respiration, leading to reduced mitochondrial length, membrane potential, calcium levels and reactive oxygen species. PLD6 depletion also disrupts mitochondrial metabolic reprogramming by inhibiting the tricarboxylic acid cycle and mitochondrial oxidative phosphorylation, resulting in altered intracellular levels of citrate and acetyl-CoA—both key modulators of Wnt/β-catenin activation. PLD6-mediated acetyl-CoA production enhances β-catenin stability by promoting its acetylation via the acetyltransferases CREB-binding protein and P300/CREB-binding-protein-associated factor. Consequently, PLD6 ablation reduces cancer stem cell-associated gene expression downstream of Wnt/β-catenin signaling, suppressing stem-like traits and chemoresistance to 5-fluorouracil. Furthermore, PLD6 depletion attenuates CRC tumorigenesis in both subcutaneous and orthotopic tumor models. Overall, PLD6 acts as an oncogenic switch by promoting mitochondria-mediated retrograde signaling, thereby regulating Wnt signaling in CRC. PLD6 drives Wnt signaling and cancer progression in CRC This study explores the role of a protein called phospholipase D6 (PLD6) in colorectal cancer (CRC). PLD6 is known to be involved in mitochondrial function, but its role in cancer was unclear. Researchers found that PLD6 is more active in CRC tissues compared with normal tissues, and higher levels of PLD6 are linked to worse outcomes for patients. Researchers used techniques such as CRISPR–Cas9 (a gene-editing tool) to modify PLD6 levels in cells and observed changes in cell behavior. They found that PLD6 promotes cancer cell growth, movement and survival by affecting mitochondrial metabolism and a signaling pathway called Wnt/β-catenin, which is important for cell growth and development. The study suggests that targeting PLD6 could be a potential strategy for treating CRC, as it may help reduce tumor growth and improve the effectiveness of chemotherapy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Insufficient labeling information regarding the appropriate age for prescribing drugs to the pediatric population is challenging. This study aimed to analyze the off‐label prescription of age‐related drugs for pediatric patients using claims data from South Korea and to assess the consistency of the approved age in South Korea, the United States, Europe, and Japan. In 2020, 1004 unique drugs were prescribed to the pediatric population in South Korea. We found that 641 drugs (63.8%, p < 0.0001) were related to off‐label prescriptions for age‐related use at least once, and the total number of off‐label prescriptions was 2,236,669 (62.2%, p < 0.0001). Chlorpheniramine (28%) was the most frequently prescribed drug for pediatric patients with an age‐related off‐label, followed by budesonide (9%) and epinephrine (9%). The degree of agreement in the approved age range for 641 off‐label drugs across countries was assessed using the overall kappa coefficient. We observed slight agreement in labeling across all countries (κ: 0.16, 95% confidence interval [CI]: 0.14–0.18). The highest degree of agreement was observed between the United States and Europe (0.41, 0.37–0.45) due to pediatric‐population‐specific legislation. South Korea showed the lowest degree of agreement with the United States and Europe (0.10, 0.06–0.14). The United States, Europe, and Japan showed fair agreement (0.23, 0.21–0.26). However, the degree of agreement between South Korea, the United States, and Japan (0.09, 0.06–0.11) and South Korea, Europe, and Japan (0.08, 0.05–0.10) was low. This study highlights the need for South Korean regulatory agencies to consider introducing pediatric legislation to prescribe evidence‐based drugs for safe and effective use.

Background: Impact of immeasurable time bias (IMTB) is yet to be examined in self-controlled designs.Methods: We conducted case-crossover, case-time-control, and case-case-time-control analyses using Korea’s healthcare database. Two empirical examples among elderly patients were used: 1) benzodiazepines-hip fracture; 2) benzodiazepines-mortality. For cases, the date of hip fracture diagnosis or death was defined as the index date, and the inherited date of their matched cases for controls or future cases. Exposure was assessed in the 1–30 day (hazard) and 61–90 day (control) windows preceding the index date. A non-missing exposure setting included in- and outpatient prescriptions and the pseudo-outpatient setting included only the outpatients. Conditional logistic regression was done to estimate odds ratios (ORs) with 95% confidence intervals (CIs), where the relative difference in OR among the two settings was calculated to quantify the IMTB.Results: The IMTB had negligible impacts in the hip fracture example in the case-crossover (non-missing exposure setting OR 1.27; 95% CI, 1.12–1.44; pseudo-outpatient setting OR 1.21; 95% CI, 1.06–1.39; magnitude 0.05), case-time-control (OR 1.18; 95% CI, 0.98–1.44; OR 1.13; 95% CI, 0.92–1.38; 0.04, respectively), and case-case-time-control analyses (OR 0.99; 95% CI, 0.80–1.23; OR 0.94; 95% CI, 0.75–1.18; 0.05, respectively). In the mortality example, IMTB had significant impacts in the case-crossover (non-missing exposure setting OR 1.44; 95% CI, 1.36–1.52; pseudo-outpatient setting OR 0.72; 95% CI, 0.67–0.78; magnitude 1.00), case-time-control (OR 1.38; 95% CI, 1.26–1.51; OR 0.68; 95% CI, 0.61–0.76; 1.03, respectively), and case-case-time-control analyses (OR 1.27; 95% CI, 1.15–1.40; OR 0.62; 95% CI, 0.55–0.69; 1.05, respectively).Conclusion: Although IMTB had negligible impacts on the drug’s effect on acute events, as these are unlikely to be accompanied with hospitalizations, it negatively biased the drug’s effect on mortality, an outcome with prodromal phases, in the three self-controlled designs.

Chimeric antigen receptor T-cell (CAR-T) therapies are a paradigm-shifting therapeutic in patients with hematological malignancies. However, some concerns remain that they may cause serious cardiovascular adverse events (AEs), for which data are scarce. In this study, gradient boosting machine algorithm-based model was fitted to identify safety signals of serious cardiovascular AEs reported for tisagenlecleucel in the World Health Organization Vigibase up until February 2024. Input dataset, comprised of positive and negative controls of tisagenlecleucel based on its labeling information and literature search, was used to train the model. Then, we implemented the model to calculate the predicted probability of serious cardiovascular AEs defined by preferred terms included in the important medical event list from European Medicine Agency. There were 467 distinct AEs from 3,280 safety cases reports for tisagenlecleucel, of which 363 (77.7%) were classified as positive controls, 66 (14.2%) as negative controls, and 37 (7.9%) as unknown AEs. The prediction model had area under the receiver operating characteristic curve of 0.76 in the test dataset application. Of the unknown AEs, six cardiovascular AEs were predicted as the safety signals: bradycardia (predicted probability 0.99), pleural effusion (0.98), pulseless electrical activity (0.89), cardiotoxicity (0.83), cardio-respiratory arrest (0.69), and acute myocardial infarction (0.58). Our findings underscore vigilant monitoring of acute cardiotoxicities with tisagenlecleucel therapy.