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Abstract Background Prescribing errors put an enormous burden on health and the economy, claiming implementation of effective methods to prevent/reduce them. Polypharmacy regimens (five or more drugs) are highly prone to unacknowledged prescribing errors, since the complex network of drug-drug interactions, guidelines and contraindications is challenging to be adequately evaluated in the prescription phase, especially if different doctors are involved. Clinical decision support systems aimed at polypharmacy evaluation may be crucial to recognize and correct prescribing errors. Methods A commercial clinical decision support system (Drug-PIN®) was applied to estimate the frequency of unrecognized prescribing errors in a group of 307 consecutive patients accessing the hospital pre-admission service of the Sant’Andrea Hospital of Rome, Italy, in the period April-June 2023. Drug-PIN® is a two-step system, first scoring the risk (low, moderate or high) associated with a certain therapy-patient pair, then allowing therapy optimization by medications exchanges. We defined prescribing errors as cases where therapy optimization could achieve consistent reduction of the Drug-PIN® calculated risk. Results Polypharmacy was present in 205 patients, and moderate to high risk for medication harm was predicted by Drug-PIN® in 91 patients (29.6%). In 58 of them (63.7%), Drug-PIN® guided optimization of the therapy could be achieved, with a statistically significant reduction of the calculated therapy-associated risk score. Patients whose therapy cannot be improved have a statistically significant higher number of used drugs. Considering the overall study population, the rate of avoidable prescribing errors was 18.89%. Conclusions Results suggest that computer-aided evaluation of medication-associated harm could be a valuable and actionable tool to identify and prevent prescribing errors in polypharmacy. We conducted the study in a Hospital pre-admission setting, which is not representative of the general population but represents a hotspot to intercept fragile population, where a consistent fraction of potentially harmful polypharmacy regimens could be promptly identified and corrected by systematic use of adequate clinical decision support tools.

Abstract Disruption of neocortical circuitry and architecture in humans causes numerous neurodevelopmental disorders. Neocortical cytoarchitecture is orchestrated by various transcription factors such as Satb2 that control target genes during strict time windows. In humans, mutations of SATB2 cause SATB2 Associated Syndrome (SAS), a multisymptomatic syndrome involving epilepsy, intellectual disability, speech delay, and craniofacial defects. Here we show that Satb2 controls neuronal migration and callosal axonal outgrowth during murine neocortical development by inducing the expression of the GPI-anchored protein, Semaphorin 7A (Sema7A). We find that Sema7A exerts this biological activity by heterodimerizing in cis with the transmembrane semaphorin, Sema4D. We could also observe that heterodimerization with Sema7A promotes targeting of Sema4D to the plasma membrane in vitro. Finally, we report an epilepsy-associated de novo mutation in Sema4D (Q497P) that inhibits normal glycosylation and plasma membrane localization of Sema4D-associated complexes. These results suggest that neuronal use of semaphorins during neocortical development is heteromeric, and a greater signaling complexity exists than was previously thought.

Abstract Abemaciclib demonstrated clinical benefit in women affected by HR+/HER2− advanced breast cancer (aBC). Drug-drug interactions (DDIs) can lead to reduced treatment efficacy or increased toxicity. This retro-prospective study aimed to evaluate outcomes, DDIs’ impact, and toxicities of abemaciclib combined with endocrine therapy in a real-world setting. Patients from 12 referral Italian hospitals with HR+/HER2− aBC who received abemaciclib were included. Clinical data about comorbidities, concurrent medications, outcomes, and adverse events (AE) were collected. Drug-PIN® (Personalized Interactions Network) is a tool recognizing the role of multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. The software was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow, and red) for each patient. Univariate and multivariate analyses were performed to identify predictors of patients’ PFS or toxicity. One hundred seventy-three patients were included. 13% of patients had >75years. The overall response rate (ORR) was 63%. The general population’s median PFS (mPFS) was 22 months (mo), while mOS were not reached. Patients treated with abemaciclib in combination with AI and fulvestrant had a mPFS of 36 and 19 mo, respectively. The most common toxicities were diarrhea, asthenia, and neutropenia detected in 63%,49%, and 49% of patients. The number of concomitant medications and comorbidities were not associated with survival outcomes (22 vs 17 mo, p = 0.068, p = 0.99). Drug-PIN tier from dark yellow to red and Drug-PIN score >12 were associated with shorter PFS compared to no/low-risk DDIs and score

Abstract Rosacea is often considered a cosmetic problem but is known to be associated with a variety of comorbidities. To identify such risks, we generated two age- and sex-matched real-world cohorts of 122,444 patients each with and without rosacea. In contrast to earlier studies, we found significant associations with malignant melanoma (OR 6.02, 95% CI 5.76–6.32). This association does not exist for an Asian sub-cohort, which could explain previous inconclusive or conflicting reports. Several strongly associated comorbidities like visual disturbances (ICD-10: H53–H54; OR 4.80, 4.68–4.92), metabolic disorders (E73–E79; OR 3.17, 3.11–3.22), joint problems (M25; OR 4.16, 4.08–4.25) and type 2 diabetes (E11; OR 1.62, 1.58–1.65) should be watched as a risk for rosacea patients. Rosacea is associated with some comorbidities and ethnicity may be a risk factor in melanoma development. The retrospective nature of this study and the sole use of ICD-10 code based filtering calls for future validation of our findings. Additionally, confounding factors such as skin type and previous UV exposure should be included in future studies.

Abstract Diseases related to the central nervous system (CNS) are major health concerns and have serious social and economic impacts. Developing new drugs for CNS-related disorders presents a major challenge as it actively involves delivering drugs into the CNS. Therefore, it is imperative to develop in silico methodologies to reliably identify potential lead compounds that can penetrate the blood–brain barrier (BBB) and help to thoroughly understand the role of different physicochemical properties fundamental to the BBB permeation of molecules. In this study, we have analysed the chemical space of the CNS drugs and compared it to the non-CNS-approved drugs. Additionally, we have collected a feature selection dataset from Muehlbacher et al. (J Comput Aided Mol Des 25(12):1095–1106, 2011. 10.1007/s10822-011-9478-1) and an in-house dataset. This information was utilised to design a molecular fingerprint that was used to train machine learning (ML) models. The best-performing models reported in this study achieved accuracies of 0.997 and 0.98, sensitivities of 1.0 and 0.992, specificities of 0.971 and 0.962, MCCs of 0.984 and 0.958, and ROC-AUCs of 0.997 and 0.999 on an imbalanced and a balanced dataset, respectively. They demonstrated overall good accuracies and sensitivities in the blind validation dataset. The reported models can be applied for fast and early screening drug-like molecules with BBB potential. Furthermore, the bbbPythoN package can be used by the research community to both produce the BBB-specific molecular fingerprints and employ the models mentioned earlier for BBB-permeability prediction.

Abstract Postoperative complications following mandibular fracture treatment vary from local wound infections to severe conditions including osteomyelitis and impaired fracture healing. Several risk factors have been associated with the development healing disorders, including fracture localisation, treatment modality and substance abuse. However, limited research on the sex-specific influence of these complications exists. A total of about 300,000 female and male patients with mandibular fractures were examined in two cohorts. After matching for confounders (age, nicotine and alcohol dependence, malnutrition, overweight, anaemia, diabetes, osteoporosis and vitamin D deficiency), two cohorts were compared with propensity-score-matched patients according to outcomes (osteomyelitis, pseudoarthrosis and disruption of the wound) within 1 year after fracture. There were significant differences between female and male patients regarding the occurrence of osteomyelitis (odds ratio [OR] [95% confidence interval]: 0.621 [0.563; 0.686]) and disruption of the wound (OR [95% confidence interval]: 0.703 [0.632; 0.782]). Surprisingly, matching for the expected confounders did not change the results substantially. Sex plays a dominant role in determining the risk stratification for postoperative osteomyelitis and disruption of the wound, after accounting for other potential confounding factors. Additional research is needed to understand the underlying mechanisms and to develop sex-specific strategies to prevent these complications.

Abstract Background The course of monkeypox can be severe. Our aim was to retrospectively compare the risk of hospital admission, the need for ventilation, sepsis, pneumonitis and death between the recent outbreak and historical outbreaks. Materials and Methods Cases of monkeypox were retrieved from the TriNetX database and assigned to either cohort I (recent outbreak between May 1st and September 16th, 2022) and cohort II (historical outbreaks before May 1st, 2022). After matching for age distribution, statistical analysis was performed. Results Of 640 patients with monkeypox 81 subjects per cohort remained after matching (mean age±standard deviation = 36.1±18.3 years). Within 56 days after diagnosis 10 patients per cohort were hospitalized (12.4%) and/or developed sepsis (12.4%). The risk of ventilation and pneumonitis were significantly lower among cohort I compared with cohort II (0 vs. 10 cases; risk difference = 12.4%; p = 0.001; Log-Rank test). No cases of death were recorded. Conclusion Even though monkeypox provides a risk of severe courses, the infection is self-limiting in most cases. Unlike past outbreaks, the risk of ventilation and pneumonitis may be relatively low among recent outbreaks.

Abstract The real-world evidence data from multiple sources which includes information on patient health status and medical behavior in routine clinical setup can give deeper insights into drugs ‘safety and efficacy. The RWE-based analysis in this study revealed a statistically significant link between biologics usage and hepatotoxicity in patients. To the best of our knowledge, this study is the first to conduct a large-scale multi-cohort analysis on the hepatotoxic profiles of biologics. Biologics are among the most prescribed medicines for several chronic inflammatory diseases. These agents target critical pathogenic pathways, but they may also have serious side effects. It is important to analyze whether biologics agents are an added concern or therapeutic opportunity. Real-world evidence (RWE) data were extracted for patients using biologics to monitor the safety and effectiveness of the biologics. All six biologics included in this analysis—are mostly highly prescribed biologics. The aim of the study was to assess the hepatotoxic profiles of subjects using different biologics. We evaluated the safety of current treatment regimens for patients in a large real-world cohort from multiple health care centers. Total number of eligible patients retrieved from the database is 38,112,285. Of these 38 million patients, 2.3 million take biologics. The primary objective was to assess the potential adverse hepatotoxic effects of the six biologics; adalimumab, trastuzumab, prevnar13, pegfilgrastim, interferon-beta1a and insulin glargine across different indications like diabetes mellitus, encounter for immunization, malignant neoplasm of breast, multiple sclerosis, malignant neoplasm of kidney, aplastic anaemias, radiation sickness, Crohn's disease, psoriasis, rheumatoid arthritis, spondylopathies. Data from patients using the six most-used biologics-adalimumab, trastuzumab, prevnar13, pegfilgrastim, interferon-beta1a and insulin glargine were retrieved from a global research network covering 250 million patients’ data from 19 countries, and assigned to the cohorts 1 and 2, respectively. The cohorts were propensity score matched for age and sex. After defining the primary outcome as “hepatotoxicity” (endpoint defined as ICD-10 code: K71 (hepatotoxic liver disease), a Kaplan–Meier survival analysis was performed, and risk ratios (RR), odds ratios (OR), and hazard ratios (HR) were determined. A total number of 2,312,655 subjects were eligible who take biologics, and after matching total cohorts accounted for 2,303,445. We have considered the clinical data as a 1:1 matched‐study design, using propensity score‐matched sub‐cohorts to better control for confounding associations that might stem from different distributions of age and gender between the whole dataset and the subset of patients. We discovered evidence supporting the hepatotoxic-causing effect of biologic drugs: (i) all biologics considered together had an OR of 1.9 (95% CI, 1.67–2.35), with (ii) Adalimumab 1.9 (95% CI, 1.72–2.20), Trastuzumab 1.7 (95% CI, 1.2–2.3), Prevnar13 2.3 (95% CI, 2.16–2.60), Pegfilgrastim 2.3 (95% CI, 2.0–2.50), Interferon-Beta1a 1.7 (95% CI, 1.18–2.51), and Insulin glargine 1.9 (95% CI, 1.8–1.99). Our findings indicate that clinicians should consider evaluating hepatic profiles of patients undergoing treatment with biologic drugs and counsel them regarding the risk of developing hepatic injury. Strengths of the study includes a large sample size and robust statistical techniques. Limitations of this study include lack of detailed information regarding clinical severity. Major biologics are associated with hepatotoxicity. We discovered evidence supporting the hepatotoxicity-causing effects of biologics: all biologics considered together had an OR of 1.9 (95% CI, 1.67–2.35).

BackgroundSex-related discrepancies in the prognosis of oral cancer patients have not been clarified. This study aimed to assess survival outcomes and potential prognostic factors in female and male patients with oral cancer.MethodsA retrospective search of the TriNetX network (TriNetX, Cambridge, Massachusetts, USA) was conducted to identify patients diagnosed with oral cancer (International Classification of Diseases (ICD)-10 codes C02–C06), within the past 20 years from the access date April 21, 2023. Patients were categorized according to sex (female vs. male). Following matching for age and risk factors such as nicotine dependence and alcohol abuse, Kaplan-Meier analysis was performed and risk, odds, and hazard ratios were calculated. Outcome variables were five-year disease-free survival (DFS) and overall survival (OS). Additionally, the female and male patient cohort were compared with regard to the novel diagnosis of depression (depressive episode, major depressive disorder, dysthymic disorder) after the tumor diagnosis.ResultsA total of 77,348 patients were assessed. After propensity score matching, 26,578 male and 26,578 female patients were included in each group (mean age 63 years). DFS (71.92% in females vs. 68.29% in males; hazard ratio (HR) 0.870; p < 0.001) and OS (77.08% in females vs. 71.74% in males; HR 0.793; p < 0.001) were significantly higher in the female cohort. However, in patients diagnosed with depression after the initial cancer diagnosis (N = 4,824), survival was worse in female patients compared to male patients (82.48% in females vs. 86.10% in males; HR 1.341; p < 0.001).ConclusionThis retrospective case-control study showed that females with oral cancer had a better DFS and OS than males. However, survival in females with a newly diagnosed depression after the oral cancer diagnosis was worse compared to those of male oral cancer patients. Depression may be a relevant prognostic factor that contributes to sex disparities in oral cancer patients.

Abstract Background Adult-onset Still’s disease (AOSD) is a multi-system, auto-inflammatory disease characterized by fever, arthralgia, typical rash, leukocytosis, sore throat, and liver dysfunction, among other symptoms. Retrospective studies about the frequencies of AOSD have shown that this disease is very rare. However, there has been an increased scientific interest in the last 2 years, as numerous case studies on AOSD have been published. These case studies describe the occurrence of AOSD after SARS-CoV-2 infection and/or COVID-19 vaccination. Methods We analyzed the incidence of AOSD to examine a potential association between AOSD and SARS-CoV-2 infection and/or COVID-19 vaccination. The TriNetX dataset consists of 90 million patients. We found 8474 AOSD cases, which we analyzed regarding SARS-CoV-2 infection and/or vaccination status. We also analyzed the cohorts considering demographic data, lab values, co-diagnoses and treatment pathways. Results We divided the AOSD cases into four cohorts: primary cohort (AOSD), Cov cohort (AOSD + SARS-CoV-2 infection), Vac cohort (AOSD + COVID-19 vaccination) and Vac + Cov cohort (AOSD + COVID-19 vaccination + SARS-CoV-2 infection). For the primary cohort, we found an annual incidence of 0.35 per 100.000. We found an association between AOSD and SARS-CoV-2 infection and/or COVID-19 vaccination. According to the numerical analysis, the incidence of AOSD doubled for the Cov cohort and Vac cohort. Moreover, the incidence of AOSD was 4.82 times higher for Vac + Cov cohort. The lab values for inflammatory markers were increased. Co-diagnoses such as rash, sore throat, and fever appeared in all AOSD cohorts, with the highest occurrences in the AOSD + COVID-19 vaccination + SARS-CoV-2 infection cohort. We identified several lines of treatments, mainly in association with adrenal corticosteroids. Conclusions This research supports the assumption of an association between AOSD and SARS-CoV-2 infection and/or COVID-19 vaccination. However, AOSD remains a rare disease and the usage of vaccines to fight the COVID-19 pandemic should not be questioned because of the increased incidence of AOSD.

Introduction: Even in times of new therapy regimes, the overall survival of patients with head and neck cancer remains low. Since the previous studies showed the beneficial effect of metformin medication on the survival of patients with cancer, our objective was to investigate if—and in which way—metformin medication affects the overall survival of patients with head and neck cancer. Methods: Clinical data pertaining to patients diagnosed with head and neck cancer (International Classification of Diseases 10 codes C00-C14, C31, and C32) were retrospectively retrieved from the TriNetX network (TriNetX, Cambridge, MA, USA). The initial cohort extracted from the network was stratified into two groups: patients on metformin medication (cohort I), and individuals not on metformin medication (cohort II). The matching criteria included age, gender, BMI, type 2 diabetes, and risk factors, such as nicotine and alcohol abuse/dependence. Kaplan–Meier analysis, risk analysis, and the calculation of odds and hazard ratios were conducted. Additionally, the Hemoglobin A1c values were subject to analysis. Results: Following matching, each cohort comprised 20,416 patients. Cohort I exhibited a higher five-year survival rate at 75.3%, in contrast to cohort II, which registered a rate of 69.8%. The odds ratio was 0.79 (95% CI = 0.75–0.83), and the hazard ratio was 0.78 (95% CI = 0.75–0.82). Conclusion: Metformin medication may correlate with improved five-year survival rates in patients with head and neck cancer. Since potentially influencing factors such as comorbidities and the initial tumor stage were not available, the results of our retrospectively conducted study must be interpreted with caution.

Abstract Background Syphilis is an infectious disease that is at least discussed to be premalignant. This potential, combined with its general pathological impact, raises the question if syphilis increases mortality in oral cancer patients. The aim of the study was to assess if the five-year survival rates among patients suffering from oral squamous cell carcinoma (OSCC) with (cohort I) and without association with syphilis (cohort II) differ. Methods Retrospective clinical data of patients diagnosed with OSCC (International Classification of Diseases [ICD]-10 codes C01–06) within the past 20 years from the access date September 25, 2021 were retrieved from the TriNetX network (TriNetX, Cambridge, Massachusetts, USA) to gain initial cohort 0. Subjects also diagnosed with syphilis (ICD-10 codes A51–53) were assigned to cohort I. Cohort II was comprised of the remaining individuals of cohort 0 by creating a group with the same number of patients as cohort I, and by matching for age and gender. Subsequently, Kaplan-Meier analysis and Cox proportional hazards regression were performed, and risk, odds and hazard ratios were calculated. Results Of a total of 73,736 patients in cohort 0, 199 individuals were each assigned to cohort I and II. During the five-year period after tumor diagnosis, 39 and 30 patients in cohort I and II died. The five-year survival probabilities did not significantly differ between the cohorts (I vs. II = 74.19% vs. 75.01%; p = 0.52; Log-Rank test), nor the risk of dying (I vs. II = 19.6% vs. 15.08%; risk difference = 4.52%; p = 0.23). The calculated risk, odds and hazard ratios were 1.3 (95% confidence interval [CI] = 0.84; 2.00), 1.37 (95% CI = 0.81; 2.31) and 1.17 (95% CI = 0.73; 1.88), respectively. Conclusions The obtained results indicate that the survival rate of individuals with OSCC might not be negatively influenced if syphilis is present/associated. However, the results need to be interpreted cautiously due to limitations related to the retrospective approach, especially as data on the tumor staging were not accessible. Trial registration Due to the retrospective nature of the study, no registration was necessary.

Background: The impact of adjuvant or neoadjuvant chemotherapy in the treatment of craniofacial bone sarcomas has not been clarified. This study aimed to assess whether survival outcomes differed between patients who underwent adjuvant or neoadjuvant chemotherapy. Methods: A retrospective search for adult patients diagnosed with malignant neoplasms of the craniofacial bones (International Classification of Diseases 10 codes C41.0–C41.1), within the past 20 years from the access date 28 April 2022, was conducted using the TriNetX network (TriNetX, Cambridge, MA, USA). Cohort I included patients who underwent adjuvant chemotherapy and cohort II included patients with neoadjuvant chemotherapy. A refined search for individuals that received common chemotherapeutic agents, such as methotrexate, doxorubicin, cisplatin, and/or ifosfamide, was conducted and patients were assigned to cohort A (adjuvant chemotherapy) and cohort B (neoadjuvant chemotherapy). Following matching for age and sex, Kaplan–Meier analysis was performed, and risk ratio, odds ratio (OR), and hazard ratio were calculated. Results: Patients were assigned to two cohorts, with 181 patients each after matching. In cohorts I and II, 55 and 41 patients died, respectively. No significant differences were found between the two cohorts regarding the 5-year survival probability (I: 59.87% versus II: 68.45%; p = 0.076; log-rank test), or the risk of dying (I: 0.304 versus II: 0.227; risk difference: 0.077; p = 0.096). The risk analysis before matching for age and sex showed a significant survival benefit in cohort II (OR: 1.586; p = 0.0295; risk difference: 0.093). After a refined query to identify patients treated with methotrexate, doxorubicin, cisplatin, and/or ifosfamide, the two cohorts included 47 patients, respectively. In cohort A (adjuvant chemotherapy), 19 patients died, whereas 12 patients died in cohort B (neoadjuvant chemotherapy) within 5 years after diagnosis. Further analysis indicated a greater survival in cohort B, but the survival probability between the cohorts did not differ significantly (A: 43.55% versus B: 54.49%; p = 0.171). Conclusion: The use of neoadjuvant chemotherapy may improve survival rates in patients with surgically treated craniofacial bone sarcomas. Due to the retrospective nature of this study, randomized controlled studies are required to derive treatment recommendations.

BackgroundThe question arises if there is an association of psycho-emotional stress and chronic soft tissue injuries caused by bruxism somatoform disorders with oral squamous cell carcinoma (OSCC).MethodsPatients with and without “somatoform disorders including psychogenic disturbances” (International Classification of Diseases [ICD]-10 code F45.8), and/or “unspecific behavioral syndromes” (F59), and/or “sleep related bruxism” (G47.63), and/or “other sleep disorders” (G47.8) were retrieved from the TriNetX network to gain cohort I. Cohort II was formed by patients without the aforementioned diagnoses, and by matching for age, gender, tobacco use, and alcohol abuse. After defining the primary outcome as “OSCC” (ICD-10 codes C00−C14), a Kaplan-Meier analysis was performed, and risk ratio (RR) and odds ratio (OR) were calculated.ResultsAfter matching, each cohort accounted for 154,639 patients (59.7% females; 40.3% males; mean current age (± standard deviation) = 43.4 ± 24.5 years). Among cohorts I and II, 907 and 763 patients, respectively, were diagnosed with OSCC within 5 years (risk of OSCC = 0.6% and 0.5%), whereby the risk difference was significant (p < 0.001; Log-Rank test). RR and OR were 1.19 (95% confidence interval (CI), lower = 1.08 and upper = 1.31) and 1.19 (95% CI, 1.08−1.31).ConclusionsPsycho-emotional stress and/or chronic mucosal injuries may play a role in carcinogenesis. However, the results need to be interpreted cautiously due to limitations of the applied approach. It may thus far only be concluded that further research is necessary to investigate hypotheses regarding psychogenic carcinogenesis and tumor formation due to chronic tissue trauma.

Background: BRAF and MEK inhibition is a successful strategy in managing BRAF-mutant melanoma, even if the treatment-related toxicity is substantial. We analyzed the role of drug–drug interactions (DDI) on the toxicity profile of anti-BRAF/anti-MEK therapy. Methods: In this multicenter, observational, and retrospective study, DDIs were assessed using Drug-PIN software (V 2/23). The association between the Drug-PIN continuous score or the Drug-PIN traffic light and the occurrence of treatment-related toxicities and oncological outcomes was evaluated. Results: In total, 177 patients with advanced BRAF-mutated melanoma undergoing BRAF/MEK targeted therapy were included. All grade toxicity was registered in 79% of patients. Cardiovascular toxicities occurred in 31 patients (17.5%). Further, 94 (55.9%) patients had comorbidities requiring specific pharmacological treatments. The median Drug-PIN score significantly increased when the target combination was added to the patient’s home therapy (p-value < 0.0001). Cardiovascular toxicity was significantly associated with the Drug-PIN score (p-value = 0.048). The Drug-PIN traffic light (p = 0.00821) and the Drug-PIN score (p = 0.0291) were seen to be significant predictors of cardiotoxicity. Patients with low-grade vs. high-grade interactions showed a better prognosis regarding overall survival (OS) (p = 0.0045) and progression-free survival (PFS) (p = 0.012). The survival analysis of the subgroup of patients with cardiological toxicity demonstrated that patients with low-grade vs. high-grade DDIs had better outcomes in terms of OS (p = 0.0012) and a trend toward significance in PFS (p = 0.068). Conclusions: DDIs emerged as a critical issue for the risk of treatment-related cardiovascular toxicity. Our findings support the utility of DDI assessment in melanoma patients treated with BRAF/MEK inhibitors.

Background: The objective of this study was to investigate the DRD2 rs1800497, rs1799732, rs1801028, DRD3 rs6280, and HTR2A rs6314, rs7997012, and rs6311 single-nucleotide polymorphism (SNP) correlations with resistance to second-generation antipsychotics (SGAs) in a real-world sample of patients with treatment-resistant mental disorders. Methods: We divided 129 participants into a high treatment resistance (HTR) group (current treatment with two SGAs, or clozapine, or classic neuroleptics for a failure of previous SGAs trials) and a low treatment resistance (LTR) group (current treatment with one atypical antipsychotic). We used Next-Generation Sequencing on DNA isolated from peripheral blood samples to analyze the polymorphisms. We performed logistic regression to search for predictors of HTR membership. Results: A diagnosis of schizophrenia significantly predicted the HTR membership compared to other diagnoses. Other predictors were the DRD3 rs6280 C|T (OR = 22.195) and T|T (OR = 18.47) vs. C|C, HTR2A rs7997012 A|G vs. A|A (OR = 6.859) and vs. G|G (OR = 2.879), and DRD2 rs1799732 I|I vs. D|I (OR = 12.079) genotypes. Conclusions: A diagnosis of schizophrenia and the DRD2 rs1799732, DRD3 rs6280, and HTR2A rs7997012 genotypes can predict high treatment resistance to SGAs.

Abstract Background The aim of this study was to evaluate the possibility of breath testing as a method of cancer detection in patients with oral squamous cell carcinoma (OSCC). Methods Breath analysis was performed in 35 OSCC patients prior to surgery. In 22 patients, a subsequent breath test was carried out after surgery. Fifty healthy subjects were evaluated in the control group. Breath sampling was standardized regarding location and patient preparation. All analyses were performed using gas chromatography coupled with ion mobility spectrometry and machine learning. Results Differences in imaging as well as in pre- and postoperative findings of OSCC patients and healthy participants were observed. Specific volatile organic compound signatures were found in OSCC patients. Samples from patients and healthy individuals could be correctly assigned using machine learning with an average accuracy of 86–90%. Conclusions Breath analysis to determine OSCC in patients is promising, and the identification of patterns and the implementation of machine learning require further assessment and optimization. Larger prospective studies are required to use the full potential of machine learning to identify disease signatures in breath volatiles.

Introduction: The overall survival among head and neck cancer patients is still low, even in a time of new therapy regimes. Regarding cancer patients’ survival, statin use has already proven to be associated with favorable survival outcomes. Our objective was to investigate the influence of statin medication on the overall survival of head and neck cancer patients. Methods: Retrospective clinical data of patients diagnosed with head and neck cancer (International Classification of Diseases codes: C00–C14) were retrieved from a real-world evidence database. The initial cohort was divided into patients with statin medication, who were assigned to building cohort I, and subjects without statin medication, who were assigned to cohort II, both matched by age, gender, and risk factors (nicotine and alcohol abuse/dependence). Subsequently, Kaplan–Meier and risk analyses were performed, and odds and hazard ratios were calculated. Results: After matching, each cohort contained 48,626 patients (cohort I = females: 15,409; (31.7%), males 33,212 (68.3%); mean age ± standard deviation (SD) at diagnosis 66.3 ± 11.4 years; cohort II = females: 15,432; (31.7%), males 33,187 (68.2%); mean age ± standard deviation (SD) at diagnosis 66.4 ± 11.5 years). Five-year survival was found to be significantly higher for cohort I, with 75.19%, respectively 70.48% for cohort II. These findings were correlated significantly with a risk of death of 15.9% (cohort I) and 17.2% (cohort II); the odds ratio was 0.91 (95% CI: 0.881–0.942) and the hazard ratio 0.80 (0.777–0.827). Conclusions: The results indicate that the five-year survival of head and neck cancer patients is significantly improved by statin medication. As this study was conducted retrospectively, our data must be interpreted with caution, especially since other potential influencing factors and the initial tumor stage were not available.

Objective: The human gut microbiome is strongly influenced by the administration of drugs, namely antibiotics. We hypothesized that the effectiveness of immunotherapy with pembrolizumab in oral squamous cell carcinoma patients is decreased by the administration of antibiotics three months before and after immunotherapy. Methods: We retrieved data from patients diagnosed with head and neck squamous cell carcinoma (HNSCC) (International Classification of Diseases [ICD]-10 codes C00-C14) and receiving immunotherapy with pembrolizumab from the TriNetX network. Two cohorts were built: patients in cohort I did not receive any antibiotics within three months before or up to three months after immunotherapy, while patients in cohort II were administered antibiotics at least once within three months before or after immunotherapy. To exclude confounders, we matched cohorts 1:1 for age, sex, secondary lymph node metastases, nicotine dependence, the insertion of feeding devices, body mass index (BMI) and severe sepsis. After defining the primary outcome as “death”, a Kaplan–Meier analysis was performed, and the risk ratio (RR), odds ratio (OR) and hazard ratio (HR) were calculated. Results: A total of 3651 patients were enrolled, and after matching, each cohort consisted of 1362 patients. Among cohorts I and II, 346 and 511 patients were deceased within one year (risk of death = 25.5 and 38.3%, respectively), whereby the risk difference was significant (p = 0.000; log-rank test). The RR was 0.68 (95% confidence interval: 0.60–0.76), OR was 0.57 (0.48–0.67) and HR was 0.58 (0.51–0.67). Conclusions: Our hypothesis was confirmed: administering antibiotics significantly decreases the drug effectiveness of immunotherapy. We hypothesize that this finding is associated with antibiotic-related changes in the gut microbiome. Prospective clinical studies on the gut microbiome in cancer patients are necessary to understand the complex ecosystem of microbiota during immunotherapy. Trial Registration: Due to the retrospective nature of the study, no registration was necessary.

Abstract Background The aim of this retrospective analysis was to evaluate the clinical and radiological outcome of revascularization therapy in traumatized permanent incisors to determine whether this approach could be implemented into clinical routine. Methods A total of 16 traumatized incisors (either avulsion or severe luxation/intrusion) with open apices (> 1 mm) that underwent revascularization following a standardized protocol were analyzed with a mean follow-up of 22 months. Radiographs and clinical parameters (such as root length, pulp space, dentin wall width, apical foramen, alveolar bone loss, ankylosis/mobility, supra−/infraposition, discoloration, probing depth) were compared pre- and postoperatively and statistically analyzed. Results Over the follow-up period, 81.3% of the teeth survived revascularization and regained sensitivity, while 18.7% failed, as they had to be extracted due to serious root resorption. Regarding radiographic outcomes a significant difference could only be found in the decrease of apical foramina (p = 0.04). The other parameters showed no significant difference between pre- and postoperative measurements. More than half of the teeth (56.3%) developed root resorptions and 31.3% displayed signs of ankylosis and 92.9% developed discolorations during follow-up. However, 85.7% of the teeth maintained the bone level and outcomes of mobility showed a significant solidification. Conclusions Revascularization is a promising approach for the treatment of immature incisors to regain sensitivity and to enhance apical closure and at least to maintain alveolar bone in terms of a socket preservation. Further studies have to be performed to determine ideal conditions (type of trauma, age, width of apical foramen) for a revascularization.

Aim of the study: Botanicals used in Traditional Chinese Medicine (TCM) are a rich source for drug discovery and provide models for multi-component drug development. To facilitate the studies of the actions of TCM drugs and expand their applications, a comprehensive database is urgently required. Methods: One online resource connects all the relevant data from multiple scientific sources and languages. Drug information from published TCM databases and the official Chinese Pharmacopoeia as well as specialized meta-websites such as Kew’s Medicinal Plant Names Service was integrated on a higher level. Results: Our database, SuperTCM, covers the aspects of TCM derived from medicinal plants, encompassing pharmacological recipes up to chemical compounds. It provides the information for 6516 TCM drugs (or “herbs”) with 5372 botanical species, 55,772 active ingredients against 543 targets in 254 KEGG pathways associated with 8634 diseases. SuperTCM is freely available at http://tcm.charite.de/supertcm.

Background: Recurrent aphthous stomatitis (RAS) is found among the most frequent diseases of the oral cavity. It is characterized by repeated formation of painful ulcers. The question has risen if due to potential tumor-promoting inflammation and sustaining proliferative signaling RAS may contribute to oral cancer. Accordingly, the aim of the study was to assess if an association of RAS and the development oral squamous cell carcinoma (OSCC) could be found in a larger cohort. As recurrent aphthous stomatitis is not classified as an oral potentially malignant disorder, it was assumed that the risk of OSCC did not differ between patients with (cohort I) and without RAS (cohort II). Methods: Retrospective clinical data of patients diagnosed with and without RAS (International Classification of Diseases (ICD)-10 code K12) within the past 20 years and a body mass index of 19–30 kg/m2 were retrieved from the TriNetX database to gain initial cohort 0. Subjects suffering from RAS were assigned to cohort I, whereby cohort II was obtained from the remaining individuals, and by matching for age, gender, as well as (history of) nicotine and alcohol dependence. After defining the primary outcome as “OSCC” (ICD-10 codes C00-C14), a Kaplan–Meier analysis was performed, and risk and odds ratios were calculated. Results: Of a total of 24,550,479 individuals in cohort 0, 72,845 subjects were each assigned to cohort I (females: 44,031 (60.44%); males: 28,814 (39.56%); mean current age (±standard deviation) = 35.51 ± 23.55 years) and II (females: 44,032 (60.45%); males: 28,813 (39.55%); mean current age (±standard deviation) = 35.51 ± 23.56 years). Among the cohorts I and II, 470 and 135 patients were diagnosed with OSCC within five years. The according risk of developing oral cancer was 0.65% and 0.18%, whereby the risk difference of 0.47% was highly significant (p < 0.0001; Log-Rank test). The RR and OR were calculated as 3.48 (95% confidence interval (CI) lower: 2.88 and upper: 4.21) and 3.50 (95% CI lower: 2.89 and upper: 4.24). Conclusions: Among the patients suffering from RAS, a significantly augmented risk of developing OSCC was found. However, it has to be emphasized that the recent literature does not provide any confirmatory evidence that supports the retrieved results. Furthermore, the findings need to be interpreted cautiously due to specific limitations that come along with the applied methods. It should thus far only be concluded that further research is necessary to evaluate hypotheses that may be retrieved from the obtained results. Despite this controversy, oral ulcers suspicious of OSCC should undergo biopsy. Trial Registration: Due to the retrospective nature of the study, no registration was necessary.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2–infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti–IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13–induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13–mediated HA synthesis in pulmonary pathology.

This Perspective examines a recent surge of information regarding the potential benefits of acid-suppression drugs in the context of COVID-19, with a particular eye on the great variability (and, thus, confusion) that has arisen across the reported findings, at least as regards the popular antacid famotidine. The degree of inconsistency and discordance reflects contradictory conclusions from independent, clinical-based studies that took roughly similar approaches, in terms of both experimental design (retrospective, observational, cohort-based, etc.) and statistical analysis workflows (propensity-score matching and stratification into sub-cohorts, etc.). The contradictions and potential confusion have ramifications for clinicians faced with choosing therapeutically optimal courses of intervention: e.g., do any potential benefits of famotidine suggest its use in a particular COVID-19 case? (If so, what administration route, dosage regimen, duration, etc. are likely optimal?) As succinctly put this March in Freedberg et al. (2021), “…several retrospective studies show relationships between famotidine and outcomes in COVID-19 and several do not.” Beyond the pressing issue of possible therapeutic indications, the conflicting data and conclusions related to famotidine must be resolved before its inclusion/integration in ontological and knowledge graph (KG)–based frameworks, which in turn are useful for drug discovery and repurposing. As a broader methodological issue, note that reconciling inconsistencies would bolster the validity of meta-analyses which draw upon the relevant data-sources. And, perhaps most broadly, developing a system for treating inconsistencies would stand to improve the qualities of both 1) real world evidence-based studies (retrospective), on the one hand, and 2) placebo-controlled, randomized multi-center clinical trials (prospective), on the other hand. In other words, a systematic approach to reconciling the two types of studies would inherently improve the quality and utility of each type of study individually.

The incidence of SARS-CoV2 infections is around 15% higher in premenopausal women compared to age matched men, yet the fatality rate from COVID-19 is significantly higher in men than women for all age strata. Sex differences have also been observed in recent epidemics including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), with SARS-CoV 2 virus infection sex differences appear more dramatic. The regulation and expression of the angiotensin converting enzyme 2 (ACE2) is the key for this special coronavirus SARS-CoV-2 to enter the cell. 17β-oestradiol increases expression level and activity of angiotensin converting enzyme-2 (ACE2) and the alternative signaling pathway of Ang II via the angiotensin II receptor type II (AT2R) and the Mas receptor is more dominant in female sex than in male sex. Maybe a hint to explain the higher infection risk in women. The same hormonal milieu plays a major role in protecting women where morbidity and mortality are concerned, since the dominant female hormone, oestradiol, has immune-modulatory properties that are likely to be protective against virus infections. It is also known that the X chromosome contains the largest number of immune-related genes, potentially conferring an advantage to women in efficient immune responsiveness. Lifestyle factors are also likely to be contributory. Premenopausal women could possibly face higher exposure to infection (hence higher infection rates) because economic conditions are often less favorable for them with less opportunity for home office work because of jobs requiring mandatory attendance. Due to the additional task of childcare, it is likely that contact times with other people will be longer. Women generally make healthier lifestyle choices, thus reducing the disease burden that confers high risk of mortality in COVID-19 infected men. This narrative review aims to present key concepts and knowledge gaps on the effects of oestrogen associated with SARS-CoV2 infection and COVID-19 disease.

The rapidly developing pandemic, known as coronavirus disease 2019 (COVID-19) and caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently spread across 213 countries and territories. This pandemic is a dire public health threat—particularly for those suffering from hypertension, cardiovascular diseases, pulmonary diseases, or diabetes; without approved treatments, it is likely to persist or recur. To facilitate the rapid discovery of inhibitors with clinical potential, we have applied ligand- and structure-based computational approaches to develop a virtual screening methodology that allows us to predict potential inhibitors. In this work, virtual screening was performed against two natural products databases, Super Natural II and Traditional Chinese Medicine. Additionally, we have used an integrated drug repurposing approach to computationally identify potential inhibitors of the main protease of SARS-CoV-2 in databases of drugs (both approved and withdrawn). Roughly 360,000 compounds were screened using various molecular fingerprints and molecular docking methods; of these, 80 docked compounds were evaluated in detail, and the 12 best hits from four datasets were further inspected via molecular dynamics simulations. Finally, toxicity and cytochrome inhibition profiles were computationally analyzed for the selected candidate compounds.

Introduction: Onset of oral lichenoid lesions (OLL) or oral lichen planus (OLP) can be rare adverse reactions to vaccines. Recently, the first solitary cases were reported after COVID-19 vaccination. The aim of the present study was to assess if an increased frequency of OLL/OLP can be found after COVID-19 vaccination within a large real-world cohort. It was assumed that the incidence of OLL/OLP was significantly higher in subjects who received COVID-19 vaccine (cohort I) compared to individuals who were not vaccinated (cohort II). Patients and Methods: Initial cohorts of 274,481 vaccinated and 9,429,892 not vaccinated patients were retrieved from the TriNetX database (TriNetX, Cambridge, Massachusetts, USA), and matched for age, gender and the frequency of use of non-steroidal anti-inflammatory drugs, beta blockers, and angiotensin-converting enzyme inhibitors. Results: After matching each cohort, we accounted for 217,863 patients. Among cohort I, 146 individuals had developed OLL/OLP within 6 days after COVID-19 vaccination (88 and 58 subjects had received mRNA- and adenovirus vector-based vaccines), whereas in cohort II, 59 patients were newly diagnosed with OLL/OLP within 6 days after having visited the clinic for any other reason. The risk of developing OLL/OLP was calculated as 0.067% vs. 0.027%, for cohorts I and II, whereby the risk difference was highly significant (p < 0.001; log-rank test). RR and OR were 2.475 (95% CI = 1.829; 3.348) and 2.476 (95% CI = 1.830; 3.350), respectively. Discussion: The hypothesis was confirmed. Accordingly, the obtained results suggest that the onset of OLL/OLP is a rare adverse drug reaction to COVID-19 vaccines, especially to mRNA vaccines. Thus far, it remains unknown if specific components of the formulations cause a type IV hypersensitive reaction corresponding to OLL, or if the immune response post vaccination triggers a T cell-driven autoimmune reaction directed against the basal layer of keratinocytes of the oral mucosa in terms of OLP. Although OLL and OLP are both classified as premalignant lesions, spontaneous remission may be expected over time, at least in the case of OLL. Therefore, the presented findings should not place any limitation toward the use of COVID-19-vaccines in broad levels of the population.

Background: The COVID-19 pandemic is being battled via the largest vaccination campaign in history, with more than eight billion doses administered thus far. Therefore, discussions about potentially adverse reactions, and broader safety concerns, are critical. The U.S. Vaccination Adverse Event Reporting System (VAERS) has recorded vaccination side effects for over 30 years. About 580,000 events have been filed for COVID-19 thus far, primarily for the Johnson & Johnson (New Jersey, USA), Pfizer/BioNTech (Mainz, Germany), and Moderna (Cambridge, USA) vaccines. Methods: Using available databases, we evaluated these three vaccines in terms of the occurrence of four generally-noticed adverse reactions—namely, cerebral venous sinus thrombosis, Guillain–Barré syndrome (a severe paralytic neuropathy), myocarditis, and pericarditis. Our statistical analysis also included a calculation of odds ratios (ORs) based on total vaccination numbers, accounting for incidence rates in the general population. Results: ORs for a number of adverse events and patient groups were (largely) increased, most notably for the occurrence of cerebral venous sinus thrombosis after vaccination with the Johnson & Johnson vaccine. The overall population OR of 10 increases to 12.5 when limited to women, and further yet (to 14.4) among women below age 50 yrs. In addition, elevated risks were found (i) for Guillain–Barré syndrome (OR of 11.6) and (ii) for myocarditis/pericarditis (ORs of 5.3/4.1, respectively) among young men (

Treatment-resistant depression (TRD) reduces affected patients’ quality of life and leads to important social health care costs. Pharmacogenomics-guided treatment (PGT) may be effective in the cure of TRD. The main aim of this study was to evaluate the clinical changes after PGT in patients with TRD (two or more recent failed psychopharmacological trials) affected by bipolar disorder (BD) or major depressive disorder (MDD) compared to a control group with treatment as usual (TAU). We based the PGT on assessing different gene polymorphisms involved in the pharmacodynamics and pharmacokinetics of drugs. We analyzed, with a repeated-measure ANOVA, the changes between the baseline and a 6 month follow-up of the efficacy index assessed through the Clinical Global Impression (CGI) scale, and depressive symptoms through the Hamilton Depression Rating Scale (HDRS). The PGT sample included 53 patients (26 BD and 27 MDD), and the TAU group included 52 patients (31 BD and 21 MDD). We found a significant within-subject effect of treatment time on symptoms and efficacy index for the whole sample, with significant improvements in the efficacy index (F = 8.544; partial η² = 0.077, p < 0.004) and clinical global impression of severity of illness (F = 6.818; partial η² = 0.062, p < 0.01) in the PGT vs. the TAU group. We also found a significantly better follow-up response (χ² = 5.479; p = 0.019) and remission (χ² = 10.351; p = 0.001) rates in the PGT vs. the TAU group. PGT may be an important option for the long-term treatment of patients with TRD affected by mood disorders, providing information that can better define drug treatment strategies and increase therapeutic improvement.

Microorganisms are diverse in their genome sequences and subsequently in their encoded metabolic pathways, which enabled them to adapt to numerous environmental conditions. They produce thousands of small molecules, many of which are volatiles in nature and play important roles in signaling in intra- and inter-species to kingdom and domain interactions, survival, or virulence. Many of these compounds have been studied, characterized, and organized in the mVOC 2.0 database. However, such dataset has not been investigated comprehensively in terms of its phylogeny to determine key volatile markers for certain taxa. It was hypothesized that some of the volatiles described in the mVOC 2.0 database could function as a phylogenetic signal since their production is conserved among certain taxa within the microbial evolutionary tree. Our meta-analysis revealed that some volatiles were produced by a large number of bacteria but not in fungal genera such as dimethyl disulfide, acetic acid, 2-nonanone, dimethyl trisulfide, 2-undecanone, isovaleric acid, 2-tridecanone, propanoic acid, and indole (common bacterial compounds). In contrast, 1-octen-3-ol, 3-octanone, and 2-pentylfuran (common fungal compounds) were produced primarily by fungal genera. Such chemical information was further confirmed by investigating genomic data of publicly available databases revealing that bacteria or fungi harbor gene families involved in these volatiles’ biosynthesis. Our phylogenetic signal testing identified 61 volatiles with a significant phylogenetic signal as demonstrated by phylogenetic D statistic P-value < 0.05. Thirty-three volatiles were phylogenetically conserved in the bacterial domain (e.g., cyclocitral) compared to 17 volatiles phylogenetically conserved in the fungal kingdom (e.g., aristolochene), whereas 11 volatiles were phylogenetically conserved in genera from both bacteria and fungi (e.g., geosmin). These volatiles belong to different chemical classes such as heterocyclic compounds, long-chain fatty acids, sesquiterpenoids, and aromatics. The performed approaches serve as a starting point to investigate less explored volatiles with potential roles in signaling, antimicrobial therapy, or diagnostics.

Ferulic acid, a well-known natural phenolic compound, is considerably reported for its hydroxyl and peroxyl radical scavenging activities. However, the antioxidant capacity of ferulic acid is limited by its relatively low solubility in hydrophobic media thereby preventing its application for autoxidation of fats and oils. To this end, several research efforts are being made to maximize the therapeutic benefits of ferulic acid and these efforts included but not limited to structural modification of ferulic acid to produce its derivatives. In this study, we synthesized ester and amide derivatives of ferulic acid and evaluated them for in vitro antioxidant potential as well as molecular docking properties. Data revealed that ferulic ester and amide derivatives had excellent antioxidant capacity and demonstrated strong inhibitory potential. Analysis of molecular docking indicated ferulic ester as potent inhibitor of target proteins in breast cancer as well as in oxidative stress. Taken together, the findings support potent antioxidant properties by these ferulic derivatives. Findings may become relevant where structural modification to enhance physico-chemical properties without compromising the antioxidant and/or medicinal potential are desirable.

More than a year has passed since the world began to fight the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the Coronavirus disease 2019 (COVID-19) pandemic, and still it spreads around the world, mutating at the same time. One of the sources of compounds with potential antiviral activity is Traditional Chinese Medicinal (TCM) plants used in China in the supportive treatment of COVID-19. Reynoutria japonica is important part of the Shu Feng Jie Du Granule/Capsule-TCM herbal formula, recommended by China Food and Drug Administration (CFDA) for treatment of patients with H1N1- and H5N9-induced acute lung injury and is also used in China to treat COVID-19, mainly combined with other remedies. In our study, 25 compounds from rhizomes of R. japonica and Reynoutria sachalinensis (related species), were docked into the binding site of SARS-CoV-2 main protease. Next, 11 of them (vanicoside A, vanicoside B, resveratrol, piceid, emodin, epicatechin, epicatechin gallate, epigallocatechin gallate, procyanidin B2, procyanidin C1, procyanidin B2 3,3’-di-O-gallate) as well as extracts and fractions from rhizomes of R. japonica and R. sachalinensis were tested in vitro using a fluorescent peptide substrate. Among the tested phytochemicals the best results were achieved for vanicoside A and vanicoside B with moderate inhibition of SARS-CoV-2 Mpro, IC50 = 23.10 µM and 43.59 µM, respectively. The butanol fractions of plants showed the strongest inhibition of SARS-CoV-2 Mpro (IC50 = 4.031 µg/mL for R. sachalinensis and IC50 = 7.877 µg/mL for R. japonica). As the main constituents of butanol fractions, besides the phenylpropanoid disaccharide esters (e.g., vanicosides), are highly polymerized procyanidins, we suppose that they could be responsible for their strong inhibitory properties. As inhibition of SARS-CoV-2 main protease could prevent the replication of the virus our research provides data that may explain the beneficial effects of R. japonica on COVID-19 and identify the most active compounds worthy of more extensive research.

(1) Background. The onset of a drug–drug interaction (DDI) may affect treatment efficacy and toxicity of advanced non-small-cell lung cancer (aNSCLC) patients during epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) use. Here we present the use of Drug-PIN® (Personalized Interactions Network) software to detect DDIs in aNSCLC patients undergoing EGFR-TKIs. (2) Methods. We enrolled patients with Stage IV aNSCLC already treated with or candidates to receive EGFR-TKIs, in any line; ECOG PS 0–2; taking at least one concomitant drug. Cancer treatments, concomitant drugs, and clinical and laboratory data were collected and inserted in Drug-PIN®. (3) Results. Ninety-two patients, median age of 68.5 years (range 43–89), were included. In total, 20 clinically relevant DDIs needing medical intervention in a total of 14 patients were identified; the 14 major DDIs were related to a high-grade interaction between TKIs and SSRIs, antipsychotics, antiepileptics, H2-receptor antagonist and calcium antagonists. A negative association between statin intake and PFS was identified (p = 0.02; HR 0.281, 95% CI 0.096–0.825). (4) Conclusions. This is the first retrospective study assessing the prevalence of DDIs, the clinical need for medical intervention and the impact of concomitant drugs on EGFR-TKIs survival in aNSCLC.

The CB1 cannabinoid receptor (CB1R) contains one of the longest N termini among class A G protein-coupled receptors. Mutagenesis studies suggest that the allosteric binding site of cannabidiol (CBD) involves residues from the N terminal domain. In order to study the allosteric binding of CBD to CB1R we modeled the whole N-terminus of this receptor using the replica exchange molecular dynamics with solute tempering (REST2) approach. Then, the obtained structures of CB1R with the N terminus were used for ligand docking. A natural cannabinoid receptor agonist, Δ9-THC, was docked to the orthosteric site and a negative allosteric modulator, CBD, to the allosteric site positioned between extracellular ends of helices TM1 and TM2. The molecular dynamics simulations were then performed for CB1R with ligands: (i) CBD together with THC, and (ii) THC-only. Analyses of the differences in the residue-residue interaction patterns between those two cases allowed us to elucidate the allosteric network responsible for the modulation of the CB1R by CBD. In addition, we identified the changes in the orthosteric binding mode of Δ9-THC, as well as the changes in its binding energy, caused by the CBD allosteric binding. We have also found that the presence of a complete N-terminal domain is essential for a stable binding of CBD in the allosteric site of CB1R as well as for the allosteric-orthosteric coupling mechanism.

Inhibition of cholinesterases remains one of a few available treatment strategies for neurodegenerative dementias such as Alzheimer’s disease and related conditions. The current study was inspired by previous data on anticholinesterase properties of diterpenoids from Perovskia atriplicifolia and other Lamiaceae species. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition by the three new natural compounds—(1R,15R)-1-acetoxycryptotanshinone (1), (1R)-1-acetoxytanshinone IIA (2), and (15R)-1-oxoaegyptinone A (3)—as well as, new for this genus, isograndifoliol (4) were assessed. Three of these compounds exhibited profound inhibition of butyrylcholinesterase (BChE) and much weaker inhibition of acetylcholinesterase (AChE). All compounds (1–4) selectively inhibited BChE (IC50 = 2.4, 7.9, 50.8, and 0.9 µM, respectively), whereas only compounds 3 and 4 moderately inhibited AChE (IC50 329.8 µM and 342.9 µM). Molecular docking and in silico toxicology prediction studies were also performed on the active compounds. Natural oxygenated norditerpenoids from the traditional Central Asian medicinal plant P. atriplicifolia are selective BChE inhibitors. Their high potential makes them useful candidate molecules for further investigation as lead compounds in the development of a natural drug against dementia caused by neurodegenerative diseases.

Vanicosides A and B are the esters of hydroxycinnamic acids with sucrose, occurring in a few plant species from the Polygonaceae family. So far, vanicosides A and B have not been evaluated for anticancer activity against human malignant melanoma. In this study, we tested these two natural products, isolated from Reynoutria sachalinensis rhizomes, against two human melanoma cell lines (amelanotic C32 cell line and melanotic A375 cell line, both bearing endogenous BRAFV600E mutation) and two normal human cell lines—keratinocytes (HaCaT) and the primary fibroblast line. Additionally, a molecular docking of vanicoside A and vanicoside B with selected targets involved in melanoma progression was performed. Cell viability was studied using an MTT assay. A RealTime-Glo™ Annexin V Apoptosis and Necrosis assay was used for monitoring programmed cell death (PCD). Vanicoside A demonstrated strong cytotoxicity against the amelanotic C32 cell line (viability of the C32 cell line was decreased to 55% after 72 h incubation with 5.0 µM of vanicoside A), significantly stronger than vanicoside B. This stronger cytotoxic activity can be attributed to an additional acetyl group in vanicoside A. No significant differences in the cytotoxicity of vanicosides were observed against the less sensitive A375 cell line. Moreover, vanicosides caused the death of melanoma cells at concentrations from 2.5 to 50 µM, without harming the primary fibroblast line. The keratinocyte cell line (HaCaT) was more sensitive to vanicosides than fibroblasts, showing a clear decrease in viability after incubation with 25 µM of vanicoside A as well as a significant phosphatidylserine (PS) exposure, but without a measurable cell death-associated fluorescence. Vanicosides induced an apoptotic death pathway in melanoma cell lines, but because of the initial loss of cell membrane integrity, an additional cell death mechanism might be involved like permeability transition pore (PTP)-mediated necrosis that needs to be explored in the future. Molecular docking indicated that both compounds bind to the active site of the BRAFV600E kinase and MEK-1 kinase; further experiments on their specific inhibitory activity of these targets should be considered.

Increase in the number of new chemicals synthesized in past decades has resulted in constant growth in the development and application of computational models for prediction of activity as well as safety profiles of the chemicals. Most of the time, such computational models and its application must deal with imbalanced chemical data. It is indeed a challenge to construct a classifier using imbalanced data set. In this study, we analyzed and validated the importance of different sampling methods over non-sampling method, to achieve a well-balanced sensitivity and specificity of a machine learning model trained on imbalanced chemical data. Additionally, this study has achieved an accuracy of 93.00%, an AUC of 0.94, F1 measure of 0.90, sensitivity of 96.00% and specificity of 91.00% using SMOTE sampling and Random Forest classifier for the prediction of Drug Induced Liver Injury (DILI). Our results suggest that, irrespective of data set used, sampling methods can have major influence on reducing the gap between sensitivity and specificity of a model. This study demonstrates the efficacy of different sampling methods for class imbalanced problem using binary chemical data sets.

Taste of a chemical compound present in food stimulates us to take in nutrients and avoid poisons. However, the perception of taste greatly depends on the genetic as well as evolutionary perspectives. The aim of this work was the development and validation of a machine learning model based on molecular fingerprints to discriminate between sweet and bitter taste of molecules. BitterSweetForest is the first open access model based on KNIME workflow that provides platform for prediction of bitter and sweet taste of chemical compounds using molecular fingerprints and Random Forest based classifier. The constructed model yielded an accuracy of 95% and an AUC of 0.98 in cross-validation. In independent test set, BitterSweetForest achieved an accuracy of 96% and an AUC of 0.98 for bitter and sweet taste prediction. The constructed model was further applied to predict the bitter and sweet taste of natural compounds, approved drugs as well as on an acute toxicity compound data set. BitterSweetForest suggests 70% of the natural product space, as bitter and 10% of the natural product space as sweet with confidence score of 0.60 and above. 77% of the approved drug set was predicted as bitter and 2% as sweet with a confidence score of 0.75 and above. Similarly, 75% of the total compounds from acute oral toxicity class were predicted only as bitter with a minimum confidence score of 0.75, revealing toxic compounds are mostly bitter. Furthermore, we applied a Bayesian based feature analysis method to discriminate the most occurring chemical features between sweet and bitter compounds using the feature space of a circular fingerprint.

Type 2 diabetes is the most prominent of all diabetes types, contributing to global morbidity and mortality. Availability and cost of treatment with little or no side effect especially in developing countries, remains a huge burden. This has led to the search of affordable alternative therapies especially from medicinal plants. In this study, the antidiabetic effect of the methanolic extract, dichloromethane (DCM), butanol (BuOH) and aqueous fractions of Clerodendrum volubile leaves were investigated in type 2 diabetic rats for their effect on glucose homeostasis, serum insulin level and hepatic biomarkers, lipid profile, pancreatic redox balance and Ca2+ levels, and β-cell distribution and function. The DCM was further fractionated to isolate the active compounds, biochanin and 5,7,4′-trimethoxykaempferol. They were investigated for their toxicity and ADMET properties, α-glucosidase and angiotensin I converting enzyme (ACE) inhibitory activities in silico. There were significant (p < 0.05) decrease in blood glucose, cholesterol, LDL-C, vLDL-C, triglyceride, AST and ALT levels in all treated groups, with DCM fraction showing the best activity. All treated rats showed significantly (p < 0.05) improved anti-oxidative activities. Treatment with the DCM fraction led to significant (p < 0.05) increased serum insulin and pancreatic Ca2+ levels, as well as improved β-cell distribution and function. DCM fraction also showed improved glucose tolerance. DCM fraction dose-dependently inhibited ACE activity. The toxicity class of the isolated compounds was predicted to be 5. They were also predicted to be potent inhibitors of cytochrome P (CYPs) 1A2, 2D6 and 3A4. They docked well with α-glucosidase and ACE. These results indicate the therapeutic potential of the plant against type 2 diabetes, with the DCM fraction being the most potent which may be attributed to the isolated flavones. It further suggests antihypertensive potentials of the DCM fraction. However, inhibition of CYPs by the flavones may suggest caution in usage with other prescribed drugs metabolized by these enzymes.

MACC1 (Metastasis Associated in Colon Cancer 1) is a key driver and prognostic biomarker for cancer progression and metastasis in a large variety of solid tumor types, particularly colorectal cancer (CRC). However, no MACC1 inhibitors have been identified yet. Therefore, we aimed to target MACC1 expression using a luciferase reporter-based high-throughput screening with the ChemBioNet library of more than 30,000 compounds. The small molecules lovastatin and rottlerin emerged as the most potent MACC1 transcriptional inhibitors. They remarkably inhibited MACC1 promoter activity and expression, resulting in reduced cell motility. Lovastatin impaired the binding of the transcription factors c-Jun and Sp1 to the MACC1 promoter, thereby inhibiting MACC1 transcription. Most importantly, in CRC-xenografted mice, lovastatin and rottlerin restricted MACC1 expression and liver metastasis. This is-to the best of our knowledge-the first identification of inhibitors restricting cancer progression and metastasis via the novel target MACC1. This drug repositioning might be of therapeutic value for CRC patients.

This work presents a generalized approach for the fast structural alignment of thousands of macromolecular structures. The method uses string representations of a macromolecular structure and a hash table that stores n-grams of a certain size for searching. To this end, macromolecular structure-to-string translators were implemented for protein and RNA structures. A query against the index is performed in two hierarchical steps to unite speed and precision. In the first step the query structure is translated into n-grams, and all target structures containing these n-grams are retrieved from the hash table. In the second step all corresponding n-grams of the query and each target structure are subsequently aligned, and after each alignment a score is calculated based on the matching n-grams of query and target. The extendable framework enables the user to query and structurally align thousands of protein and RNA structures on a commodity machine and is available as open source from http://lajolla.sf.net.

Immune mediated adverse drug reactions (IM-ADRs) remain a significant source of patient morbidity that have more recently been shown to be associated with specific class I and/or II human leukocyte antigen (HLA) alleles. Abacavir-induced hypersensitivity syndrome is a CD8+ T cell dependent IM-ADR that is exclusively mediated by HLA-B*57:01. We and others have previously shown that abacavir can occupy the floor of the peptide binding groove of HLA-B*57:01 molecules, increasing the affinity of certain self peptides resulting in an altered peptide-binding repertoire. Here, we have identified another drug, acyclovir, which appears to act in a similar fashion. As with abacavir, acyclovir showed a dose dependent increase in affinity for peptides with valine and isoleucine at their C-terminus. In agreement with the binding studies, HLA-B*57:01 peptide-elution studies performed in the presence of acyclovir revealed an increased number of endogenously bound peptides with a C-terminal isoleucine. Accordingly, we have hypothesized that acyclovir acts by the same mechanism as abacavir, although our data also suggest the overall effect is much smaller: the largest changes of peptide affinity for acyclovir were 2-5 fold, whereas for abacavir this effect was as much as 1000-fold. Unlike abacavir, acyclovir is not known to cause IM-ADRs. We conclude that the modest effect of acyclovir on HLA binding affinity in contrast to the large effect of abacavir is insufficient to trigger a hypersensitivity syndrome. We further support this by functional in vitro studies where acyclovir, unlike abacavir, was unable to produce an increase in IFN-γ upon expansion of HLA-B*57:01+ PBMCs from healthy donors. Using abacavir and acyclovir as examples we therefore propose an in vitro pre-clinical screening strategy, whereby thresholds can be applied to MHC-peptide binding assays to determine the likelihood that a drug could cause a clinically relevant IM-ADR.

BackgroundMicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. It has been proposed that miRNAs play an important role in cancer development and progression. Their ability to affect multiple gene pathways by targeting various mRNAs makes them an interesting class of regulators.Methodology/principal findingsWe have developed an algorithm, Classification based Analysis of Paired Expression data of RNA (CAPE RNA), which is capable of identifying altered miRNA-mRNA regulation between tissues samples that assigns interaction states to each sample without preexisting stratification of groups. The distribution of the assigned interaction states compared to given experimental groups is used to assess the quality of a predicted interaction. We demonstrate the applicability of our approach by analyzing urothelial carcinoma and normal bladder tissue samples derived from 24 patients. Using our approach, normal and tumor tissue samples as well as different stages of tumor progression were successfully stratified. Also, our results suggest interesting differentially regulated miRNA-mRNA interactions associated with bladder tumor progression.Conclusions/significanceThe need for tools that allow an integrative analysis of microRNA and mRNA expression data has been addressed. With this study, we provide an algorithm that emphasizes on the distribution of samples to rank differentially regulated miRNA-mRNA interactions. This is a new point of view compared to current approaches. From bootstrapping analysis, our ranking yields features that build strong classifiers. Further analysis reveals genes identified as differentially regulated by miRNAs to be enriched in cancer pathways, thus suggesting biologically interesting interactions.

The cytochrome P450 (CYP) enzymes are major players in drug metabolism. More than 2,000 mutations have been described, and certain single nucleotide polymorphisms (SNPs) have been shown to have a large impact on CYP activity. Therefore, CYPs play an important role in inter-individual drug response and their genetic variability should be factored into personalized medicine. To identify the most relevant polymorphisms in human CYPs, a text mining approach was used. We investigated their frequencies in different ethnic groups, the number of drugs that are metabolized by each CYP, the impact of CYP SNPs, as well as CYP expression patterns in different tissues. The most important polymorphic CYPs were found to be 1A2, 2D6, 2C9 and 2C19. Thirty-four common allele variants in Caucasians led to altered enzyme activity. To compare the relevant Caucasian SNPs with those of other ethnicities a search in 1,000 individual genomes was undertaken. We found 199 non-synonymous SNPs with frequencies over one percent in the 1,000 genomes, many of them not described so far. With knowledge of frequent mutations and their impact on CYP activities, it may be possible to predict patient response to certain drugs, as well as adverse side effects. With improved availability of genotyping, our data may provide a resource for an understanding of the effects of specific SNPs in CYPs, enabling the selection of a more personalized treatment regimen.

BACKGROUND: In general, drug metabolism has to be considered to avoid adverse effects and ineffective therapy. In particular, chemotherapeutic drug cocktails strain drug metabolizing enzymes especially the cytochrome P450 family (CYP). Furthermore, a number of important chemotherapeutic drugs such as cyclophosphamide, ifosfamide, tamoxifen or procarbazine are administered as prodrugs and have to be activated by CYP. Therefore, the genetic variability of these enzymes should be taken into account to design appropriate therapeutic regimens to avoid inadequate drug administration, toxicity and inefficiency. OBJECTIVE: The aim of this work was to find drug interactions and to avoid side effects or ineffective therapy in chemotherapy. DATA SOURCES AND METHODS: Information on drug administration in the therapy of leukemia and their drug metabolism was collected from scientific literature and various web resources. We carried out an automated textmining approach. Abstracts of PubMed were filtered for relevant articles using specific keywords. Abstracts were automatically screened for antineoplastic drugs and their synonyms in combination with a set of human CYPs in title or abstract. RESULTS: We present a comprehensive analysis of over 100 common cancer treatment regimens regarding drug-drug interactions and present alternatives avoiding CYP overload. Typical concomitant medication, e.g. antiemetics or antibiotics is a preferred subject to improvement. A webtool, which allows drug cocktail optimization was developed and is publicly available on http://bioinformatics.charite.de/chemotherapy.

Peptide vaccination in cancer therapy is a promising alternative to conventional methods. However, the parameters for this personalized treatment are difficult to access experimentally. In this respect, in silico models can help to narrow down the parameter space or to explain certain phenomena at a systems level. Herein, we develop two empirical interaction potentials specific to B-cell and T-cell receptor complexes and validate their applicability in comparison to a more general potential. The interaction potentials are applied to the model VaccImm which simulates the immune response against solid tumors under peptide vaccination therapy. This multi-agent system is derived from another immune system simulator (C-ImmSim) and now includes a module that enables the amino acid sequence of immune receptors and their ligands to be taken into account. The multi-agent approach is combined with approved methods for prediction of major histocompatibility complex (MHC)-binding peptides and the newly developed interaction potentials. In the analysis, we critically assess the impact of the different modules on the simulation with VaccImm and how they influence each other. In addition, we explore the reasons for failures in inducing an immune response by examining the activation states of the immune cell populations in detail.In summary, the present work introduces immune-specific interaction potentials and their application to the agent-based model VaccImm which simulates peptide vaccination in cancer therapy.

Cancer is one of the most challenging diseases of today. Optimization of standard treatment protocols consisting of the main columns of chemo- and radiotherapy followed or preceded by surgical intervention is often limited by toxic side effects and induction of concomitant malignancies and/or development of resistant mechanisms. This requires the development of therapeutic strategies which are as effective as standard therapies but permit the patients a life without severe negative side effects. Along this line, the development of immunotherapy in general and the innovative concept of DNA vaccination in particular may provide a venue to achieve this goal. Using the patient's own immune system by activation of humoral and cellular immune responses to target the cancer cells has shown first promising results in clinical trials and may allow reduced toxicity standard therapy regimen in the future. The main challenge of this concept is to transfer the plethora of convincing preclinical and early clinical results to an effective treatment of patients.