Herb-drug interactions: a novel algorithm-assisted information system for pharmacokinetic drug interactions with herbal supplements in cancer treatment.

PURPOSE: To develop a system to estimate the risk of herb-drug interactions that includes the available evidence from clinical and laboratory studies, transparently delineates the algorithm for the risk estimation, could be used in practice settings and allows for adaptation and update. METHODS: We systematically searched Drugbank, Transformer, Drug Information Handbook, European and German Pharmacopoeia and MEDLINE for studies on herb-drug interactions of five common medicinal plants (coneflower, ginseng, milk thistle, mistletoe and St. John's wort). A diverse set of data were independently extracted by two researchers and subsequently analysed by a newly developed algorithm. Results are displayed in the form of interaction risk categories. The development of the algorithm was guided by an expert panel consensus process. RESULTS: From 882 publications retrieved by the search, 154 studies were eligible and provided 529 data sets on herbal interactions. The developed algorithm prioritises results from clinical trials over case reports over in vitro investigations and considers type of study, consistency of study results and study outcome for clinical trials as well as identification, permeability, bioavailability, and interaction potency of an identified herbal perpetrator for in vitro investigations. Risk categories were assigned to and dynamically visualised in a colour-coded matrix format. CONCLUSIONS: The novel algorithm allows to transparently generate and dynamically display herb-drug interaction risks based on the available evidence from clinical and laboratory pharmacologic studies. It provides health professionals with readily available and easy updatable information about the risk of pharmacokinetic interactions between herbs and oncologic drugs.

Clinical Manifestations of Infections with the Omicron Sub-Lineages BA.1, BA.2, and BA.5: A Retrospective Follow-Up Analysis of Public Health Data from Mecklenburg-Western Pomerania, Germany.

The Omicron variants BA.1, BA.2, and BA.5 caused several waves of SARS-CoV-2 in Germany in 2022. In this comparative study, public health data on SARS-CoV-2 infections from Mecklenburg-Western Pomerania, Germany, between January and October 2022 were examined retrospectively using Pearson's chi-squared tests and Fisher's exact tests for testing for statistical significance. Compared to BA.5 infections, BA.1 and BA.2 infections affected younger individuals aged up to 19 years significantly more often, whereas BA.5 infections occurred significantly more frequently in patients between 40 and 59 years of age when compared to BA.1 and BA.2. Infections with all three variants predominantly caused flu-like symptoms; nevertheless, there were significant differences between the reported symptoms of BA.1, BA.2, and BA.5 infections. Especially, the symptoms of 'fever', 'severe feeling of sickness', 'loss of taste', and 'loss of smell' were significantly more often present in patients with BA.5 infections compared to BA.1 and BA.2 cases. Additionally, BA.2 and BA.5 cases reported significantly more often the symptoms of 'runny nose' and 'cough' than BA.1-infected cases. Our findings indicate remarkable differences in the clinical presentations among the sub-lineages, especially in BA.5 infections. Furthermore, the study demonstrates a powerful tool to link epidemiological data with genetic data in order to investigate their potential impact on public health.

Neighbourhood watch: genomic epidemiology of SARS-CoV-2 variants circulating in a German federal state, Mecklenburg-Western Pomerania, in 2020-2022.

ABSTRACTGlobal and even national genome surveillance approaches do not provide the resolution necessary for rapid and accurate direct response by local public health authorities. Hence, a regional network of microbiological laboratories in collaboration with the health departments of all districts of the German federal state of Mecklenburg-Western Pomerania (M-V) was formed to investigate the regional molecular epidemiology of circulating SARS-CoV-2 lineages between 11/2020 and 03/2022. More than 4750 samples from all M-V counties were sequenced using Illumina and Nanopore technologies. Overall, 3493 (73.5%) sequences fulfilled quality criteria for time-resolved and/or spatially-resolved maximum likelihood phylogenic analyses and k-mean/ median clustering (KMC). We identified 116 different Pangolin virus lineages that can be assigned to 16 Nextstrain clades. The ten most frequently detected virus lineages belonged to B.1.1.7, AY.122, AY.43, BA.1, B.1.617.2, BA.1.1, AY.9.2, AY.4, P.1 and AY.126. Time-resolved phylogenetic analyses showed the occurrence of virus clades as determined worldwide, but with a substantial delay of one to two months. Further spatio-temporal phylogenetic analyses revealed a regional outbreak of a Gamma variant limited to western M-V counties. Finally, KMC elucidated a successive introduction of the various virus lineages into M-V, possibly triggered by vacation periods with increased (inter-) national travel activities. The COVID-19 pandemic in M-V was shaped by a combination of several SARS-CoV-2 introductions, lockdown measures, restrictive quarantine of patients and the lineage specific replication rate. Complementing global and national surveillance, regional surveillance adds value by providing a higher level of surveillance resolution tailored to local health authorities.

Differences in Clinical Presentations of Omicron Infections with the Lineages BA.2 and BA.5 in Mecklenburg-Western Pomerania, Germany, between April and July 2022.

Knowledge on differences in the severity and symptoms of infections with the SARS-CoV-2 Omicron variants BA.2 (Pango lineage B.1.529.2) and BA.5 (Pango lineage B.1.529.5) is still scarce. We investigated epidemiological data available from the public health authorities in Mecklenburg-Western Pomerania, Northeast Germany, between April and July 2022 retrospectively. Comparative analyses revealed significant differences between recorded symptoms of BA.2 and BA.5 infected individuals and found strong correlations of associations between symptoms. In particular, the symptoms 'chills or sweating', 'freeze' and 'runny nose' were more frequently reported in BA.2 infections. In contrast, 'other clinical symptoms' appeared more frequently in Omicron infections with BA.5. However, the results obtained in this study provide no evidence that BA.5 has a higher pathogenicity or causes a more severe course of infection than BA.2. To our knowledge, this is the first report on clinical differences between the current Omicron variants BA.2 and BA.5 using public health data. Our study highlights the value of timely investigations of data collected by public health authorities to gather detailed information on the clinical presentation of different SARS-CoV-2 subvariants at an early stage.

Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line.

Exploring mechanisms of drug resistance to targeted small molecule drugs is critical for an extended clinical benefit in the treatment of non-small cell lung cancer (NSCLC) patients carrying activating epidermal growth factor receptor (EGFR) mutations. Here, we identified constitutive cell proliferation regulating inhibitor of protein phosphatase 2A (CIP2A) in the HCC4006rErlo0.5 NSCLC cell line adapted to erlotinib as a model of acquired drug resistance. Constitutive CIP2A resulted in a constitutive activation of Akt signaling. The proteasome inhibitor bortezomib was able to reduce CIP2A levels, which resulted in an activation of protein phosphatase 2A and deactivation of Akt. Combination experiments with erlotinib and bortezomib revealed a lack of interaction between the two drugs. However, the effect size of bortezomib was higher in HCC4006rErlo0.5, compared to the erlotinib-sensitive HCC4006 cells, as indicated by an increase in Emax (0.911 (95%CI 0.867-0.954) vs. 0.585 (95%CI 0.568-0.622), respectively) and decrease in EC50 (52.4 µM (95%CI 46.1-58.8 µM) vs. 73.0 µM (95%CI 60.4-111 µM), respectively) in the concentration-effect model, an earlier onset of cell death induction, and a reduced colony surviving fraction (0.38 ± 0.18 vs. 0.95 ± 0.25, respectively, n = 3, p < 0.05). Therefore, modulation of CIP2A with bortezomib could be an interesting approach to overcome drug resistance to erlotinib treatment in NSCLC.