Interference of Herbal Medicine with Axitinib in Metastatic Renal Cell Cancer Treatment: A Case Study.

Introduction: The awareness and the clinical relevance of the potential interactions between standard and complementary medicine are increasing in medical oncology. Nonetheless, the research and experience of the efficacy, safety, and toxicity of herbal substances are poorly documented. Case Presentation: Here, we report the case of a 68-year-old female patient who had been diagnosed with advanced renal cell cancer with metastasis in the liver and pancreas and had undergone surgical resection with hemi-hepatectomy and resection of metastasis in the pancreas in November 2021. Thereafter, chemotherapy was immediately initiated with three-weekly infusions of pembrolizumab and daily intake of the tyrosine kinase inhibitor axitinib. Surprisingly, 3 months after initiation of systemic treatment, the patient developed early progression and metastasis in the liver, which was then treated with selective internal radiotherapy. Despite continued axitinib and pembrolizumab treatment, a short-term follow-up in November 2022 revealed another metastatic lesion in her pancreas. Due to the presumed lack of response to treatment, the plasma concentration of axitinib was measured and found to demonstrate subtherapeutic levels of exposure. Upon extended anamnesis, the patient reported regular intake of herbal substances prescribed by her oncology acupuncturist for gastrointestinal complaints associated with the primary operation. Conclusion: Further clinical-pharmacological workup strikingly demonstrated a reduction of the therapeutic concentration of axitinib of about 90%, likely caused by herbal drugs such as Dang gui and Bai zhu.

Testing Lennard-Jones clusters for optimality.

This note advertises a simple necessary condition for optimality that any list N ↦ vx(N) of computer-generated putative lowest average pair energies vx(N) of clusters that consist of N monomers has to satisfy whenever the monomers interact with each other through pair forces satisfying Newton's "action equals re-action." These can be quite complicated, as, for instance, in the TIP5P model with five-site potential for a rigid tetrahedral-shaped H2O monomer of water, or as simple as the Lennard-Jones single-site potential for the center of an atomic monomer (which is also used for one site of the H2O monomer in the TIP5P model, which in addition has four peripheral sites with Coulomb potentials). The empirical usefulness of the necessary condition is demonstrated by testing a list of publicly available Lennard-Jones cluster data that have been pooled from 17 sources, covering the interval 2 ≤ N ≤ 1610 without gaps. The data point for N = 447 failed this test, meaning the listed 447-particle Lennard-Jones cluster energy was not optimal. To implement this test for optimality in search algorithms for putatively optimal configurations is an easy task. Publishing only the data that pass the test would increase the odds that these are actually optimal, without guaranteeing it, though.

Multilingual RECIST classification of radiology reports using supervised learning.

Objectives: The objective of this study is the exploration of Artificial Intelligence and Natural Language Processing techniques to support the automatic assignment of the four Response Evaluation Criteria in Solid Tumors (RECIST) scales based on radiology reports. We also aim at evaluating how languages and institutional specificities of Swiss teaching hospitals are likely to affect the quality of the classification in French and German languages. Methods: In our approach, 7 machine learning methods were evaluated to establish a strong baseline. Then, robust models were built, fine-tuned according to the language (French and German), and compared with the expert annotation. Results: The best strategies yield average F1-scores of 90% and 86% respectively for the 2-classes (Progressive/Non-progressive) and the 4-classes (Progressive Disease, Stable Disease, Partial Response, Complete Response) RECIST classification tasks. Conclusions: These results are competitive with the manual labeling as measured by Matthew's correlation coefficient and Cohen's Kappa (79% and 76%). On this basis, we confirm the capacity of specific models to generalize on new unseen data and we assess the impact of using Pre-trained Language Models (PLMs) on the accuracy of the classifiers.

Targeting ALK in Neuroendocrine Tumors of the Lung.

Background: Anaplastic lymphoma kinase (ALK) rearrangements are known oncogenic drivers in non-small cell lung cancer (NSCLC). Few case reports described the occurrence of such rearrangements in large cell neuroendocrine carcinomas (LCNECs) of the lung without information on clinical responses to ALK tyrosine kinase inhibitors (TKIs) in these cases. Currently, neuroendocrine tumors of the lungs are not screened for ALK rearrangements. Methods: To illustrate the clinical impact of molecular characterization in LCNECs, we report the disease course in three patients with ALK-rearranged metastatic LCNEC from our clinical routine, as well as their treatment response to ALK TKIs (index cases). To gain insight into the prevalence of ALK rearrangements in neuroendocrine tumors of the lung, we analyzed a retrospective cohort of 436 tumor biopsies including LCNEC (n = 61), small cell lung cancer (SCLC) (n = 206), typical (n = 91) and atypical (n = 69) carcinoids, and mixed histology (n = 9) for the presence of ALK rearrangements using a sequential diagnostic algorithm. ALK immunohistochemistry (IHC) was evaluable in 362 cases; fluorescence in situ hybridization (FISH) was evaluable in 28 out of the 35 IHC-positive cases, followed by next-generation sequencing (NGS) that was available in 12 cases. Results: Within the retrospective cohort, ALK IHC was positive in 35 out of 362 (9.7%) evaluable samples. FISH was positive in 3 out of the 28 (10.7%) evaluable cases: 2 with atypical carcinoids and 1 with LCNEC. Additionally, the 3 index cases showed positive ALK IHC, which was confirmed by NGS. Within the retrospective cohort, NGS confirmed the presence of an ALK genomic rearrangement in one FISH-positive atypical carcinoid where material was sufficient for sequencing. Two out of three patients with metastatic ALK-rearranged LCNEC received up-front treatment with the ALK TKI alectinib and showed rapid tumor response at all metastatic sites, including multiple brain metastases. Conclusions: ALK rearrangements represent rare but targetable oncogenic driver alterations in LCNEC. Contrarily to NSCLC, the detection of ALK rearrangements in neuroendocrine tumors of the lung is challenging, since ALK IHC can lead to false-positive results and therefore needs confirmation by FISH or NGS. Up-front comprehensive molecular profiling with NGS should be performed in metastatic LCNEC in order not to miss actionable genomic alterations.

Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells.

Systematic exploration of cancer cell vulnerabilities can inform the development of novel cancer therapeutics. Here, through analysis of genome-scale loss-of-function datasets, we identify adenosine deaminase acting on RNA (ADAR or ADAR1) as an essential gene for the survival of a subset of cancer cell lines. ADAR1-dependent cell lines display increased expression of interferon-stimulated genes. Activation of type I interferon signaling in the context of ADAR1 deficiency can induce cell lethality in non-ADAR1-dependent cell lines. ADAR deletion causes activation of the double-stranded RNA sensor, protein kinase R (PKR). Disruption of PKR signaling, through inactivation of PKR or overexpression of either a wildtype or catalytically inactive mutant version of the p150 isoform of ADAR1, partially rescues cell lethality after ADAR1 loss, suggesting that both catalytic and non-enzymatic functions of ADAR1 may contribute to preventing PKR-mediated cell lethality. Together, these data nominate ADAR1 as a potential therapeutic target in a subset of cancers.

NRAS mutations in cutaneous T cell lymphoma (CTCL) sensitize tumors towards treatment with the multikinase inhibitor Sorafenib.

Therapy of cutaneous T cell lymphoma (CTCL) is complicated by a distinct resistance of the malignant T cells towards apoptosis that can be caused by NRAS mutations in late-stage patients. These mutations correlate with decreased overall survival, but sensitize the respective CTCL cells towards MEK-inhibition-induced apoptosis which represents a promising novel therapeutic target in CTCL. Here, we show that the multi-kinase inhibitor Sorafenib induces apoptosis in NRAS-mutated CTCL cells. CTCL cell lines and to a minor extent primary T cells from Sézary patients without NRAS mutations are also affected by Sorafenib-induced apoptosis suggesting a sensitizing role of NRAS mutations for Sorafenib-induced apoptosis. When combining Sorafenib with the established CTCL medication Vorinostat we detected an increase in cell death sensitivity in CTCL cells. The combination treatment acted synergistically in apoptosis induction in both non-mutant and mutant CTCL cells. Mechanistically, this synergistic apoptosis induction by Sorafenib and Vorinostat is based on the downregulation of the anti-apoptotic protein Mcl-1, but not of other Bcl-2 family members. Taken together, these findings suggest that Sorafenib in combination with Vorinostat represents a novel therapeutic approach for the treatment of CTCL patients.

Correction: Targeting the mTOR Complex by Everolimus in NRAS Mutant Neuroblastoma.

[This corrects the article DOI: 10.1371/journal.pone.0147682.].

Efficacious and save use of biosimilar filgrastim for hematopoietic progenitor cell chemo-mobilization with vinorelbine in multiple myeloma patients.

Biosimilars are increasingly being licensed as equipotent drugs, although efficacy and safety data are not available for all clinical indications. Accordingly, the efficacy of the biosimilar filgrastim Zarzio® combined with vinorelbine for chemo-mobilization of CD34+ hematopoietic progenitor cells (HPC) in patients with multiple myeloma has not been evaluated yet. We compared the efficacy of vinorelbine combined with this biosimilar filgrastim for HPC mobilization to vinorelbine plus original filgrastim (Neupogen®). Overall, 105 multiple myeloma patients received vinorelbine 35 mg/m2 intravenously on day 1 and either original filgrastim (n = 61;58%) or biosimilar filgrastim (n = 44;42%) at a dose of 5 µg per kg body weight (BW) twice daily subcutaneously starting day 4 until the end of the collection procedure. Leukapheresis was scheduled to start on day 8 and performed for a maximum of three consecutive days until at least 4 × 106 HPC/kg BW were collected. All patients proceeded to leukapheresis. In 102 (97%) patients the leukapheresis sessions were started as planned at day 8. The median number of collected HPC was 7.3 × 106 /kg BW (0.2-18.3) with original filgrastim compared to 9 × 106 /kg BW (4.2-23.8) with the biosimilar filgrastim (P = 0.16). HPC collection was successful in 57 (93%) of 61 patients of the original group and in all 44 (100%) patients of the biosimilar group (P = 0.14). No differences were observed regarding side effects. Duration of neutrophil engraftment after autologous HPC transplantation was similar between the two groups (P = 0.17). Biosimilar and original filgrastim achieve comparable results in combination with vinorelbine regarding HPC mobilization and transplantation outcome in multiple myeloma patients. J. Clin. Apheresis 32:21-26, 2017. © 2016 Wiley Periodicals, Inc.

Identification of oncogenic driver mutations by genome-wide CRISPR-Cas9 dropout screening.

BACKGROUND: Genome-wide CRISPR-Cas9 dropout screens can identify genes whose knockout affects cell viability. Recent CRISPR screens detected thousands of essential genes required for cellular survival and key cellular processes; however discovering novel lineage-specific genetic dependencies from the many hits still remains a challenge. RESULTS: To assess whether CRISPR-Cas9 dropout screens can help identify cancer dependencies, we screened two human cancer cell lines carrying known and distinct oncogenic mutations using a genome-wide sgRNA library. We found that the gRNA targeting the driver mutation EGFR was one of the highest-ranking candidates in the EGFR-mutant HCC-827 lung adenocarcinoma cell line. Likewise, sgRNAs for NRAS and MAP2K1 (MEK1), a downstream kinase of mutant NRAS, were identified among the top hits in the NRAS-mutant neuroblastoma cell line CHP-212. Depletion of these genes targeted by the sgRNAs strongly correlated with the sensitivity to specific kinase inhibitors of the EGFR or RAS pathway in cell viability assays. In addition, we describe other dependencies such as TBK1 in HCC-827 cells and TRIB2 in CHP-212 cells which merit further investigation. CONCLUSIONS: We show that genome-wide CRISPR dropout screens are suitable for the identification of oncogenic drivers and other essential genes.

Targeting the mTOR Complex by Everolimus in NRAS Mutant Neuroblastoma.

High-risk neuroblastoma remains lethal in about 50% of patients despite multimodal treatment. Recent attempts to identify molecular targets for specific therapies have shown that Neuroblastoma RAS (NRAS) is significantly mutated in a small number of patients. However, few inhibitors for the potential treatment for NRAS mutant neuroblastoma have been investigated so far. In this in-vitro study, we show that MEK inhibitors AZD6244, MEK162 and PD0325901 block cell growth in NRAS mutant neuroblastoma cell lines but not in NRAS wild-type cell lines. Several studies show that mutant NRAS leads to PI3K pathway activation and combined inhibitors of PI3K/mTOR effectively block cell growth. However, we observed the combination of MEK inhibitors with PI3K or AKT inhibitors did not show synergestic effects on cell growth. Thus, we tested single mTOR inhibitors Everolimus and AZD8055. Interestingly, Everolimus and AZD8055 alone were sufficient to block cell growth in NRAS mutant cell lines but not in wild-type cell lines. We found that Everolimus alone induced apoptosis in NRAS mutant neuroblastoma. Furthermore, the combination of mTOR and MEK inhibitors resulted in synergistic growth inhibition. Taken together, our results show that NRAS mutant neuroblastoma can be targeted by clinically available Everolimus alone or in combination with MEK inhibitors which could impact future clinical studies.

Targeting the RAS pathway by mitogen-activated protein kinase inhibitors.

Targeting of oncogenic driver mutations with small-molecule inhibitors resulted in powerful treatment options for cancer patients in recent years. The RAS (rat sarcoma) pathway is among the most frequently mutated pathways in human cancer. Whereas targeting mutant Kirsten RAS (KRAS) remains difficult, mutant B rapidly accelerated fibrosarcoma (BRAF) kinase is an established drug target in cancer. Now data show that neuroblastoma RAS (NRAS) and even Harvey RAS (HRAS) mutations could be predictive markers for treatment with mitogen-activated protein kinase (MEK) inhibitors. This review discusses recent preclinical and clinical studies of MEK inhibitors in BRAF and RAS mutant cancer.

Mutant HRAS as novel target for MEK and mTOR inhibitors.

HRAS is a frequently mutated oncogene in cancer. However, mutant HRAS as drug target has not been investigated so far. Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer. HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901. Further, we found that MEK inhibitors induce apoptosis in mutant HRAS cell lines but not in cell lines lacking RAS mutations. In addition, knockdown of HRAS by siRNA blocked cell growth in mutant HRAS cell lines. Inhibition of the PI3K pathway alone or in combination with MEK inhibitors did not alter signaling nor had an impact on viability. However, inhibition of mTOR or combined inhibition of MEK and mTOR reduced cell growth in a synergistic manner. Finally, Ba/F3 cells transformed with mutant HRAS isoforms Q61L, Q61R and G12V demonstrated equal sensitivity towards MEK and mTOR inhibition. Our results show that HRAS mutations in cancer activate the RAS and mTOR pathways which might serve as a therapeutic option for patients with HRAS mutant tumors.

Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters.

AIMS: Metformin pharmacokinetics depends on the presence and activity of membrane-bound drug transporters and may be affected by transport inhibitors. The aim of this study was to investigate the effects of trimethoprim on metformin pharmacokinetics and genetic modulation by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) polymorphisms. METHODS: Twenty-four healthy volunteers received metformin 500 mg three times daily for 10 days and trimethoprim 200 mg twice daily from day 5 to 10. Effects of trimethoprim on steady-state metformin pharmacokinetics were analysed. RESULTS: In the population as a whole, trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l h(-1) and renal metformin clearance from 31 to 21 l h(-1) , and prolonged half-life from 2.7 to 3.6 h (all P < 0.01). This resulted in an increase in the maximal plasma concentration by 38% and in the area under the plasma concentration-time curve by 37%. In volunteers polymorphic for both OCT2 and MATE1, trimethoprim had no relevant inhibitory effects on metformin kinetics. Trimethoprim was associated with a decrease in creatinine clearance from 133 to 106 ml min(-1) (P < 0.01) and an increase in plasma lactate from 0.94 to 1.2 mmol l(-1) (P = 0.016). CONCLUSIONS: The extent of inhibition by trimethoprim was moderate, but might be clinically relevant in patients with borderline renal function or high-dose metformin.

High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade.

Cutaneous T-cell lymphomas (CTCLs) are malignancies of skin-homing lymphoid cells, which have so far not been investigated thoroughly for common oncogenic mutations. We screened 90 biopsy specimens from CTCL patients (41 mycosis fungoides, 36 Sézary syndrome, and 13 non-mycosis fungoides/Sézary syndrome CTCL) for somatic mutations using OncoMap technology. We detected oncogenic mutations for the RAS pathway in 4 of 90 samples. One mycosis fungoides and one pleomorphic CTCL harbored a KRAS(G13D) mutation; one Sézary syndrome and one CD30(+) CTCL harbored a NRAS(Q61K) amino acid change. All mutations were found in stage IV patients (4 of 42) who showed significantly decreased overall survival compared with stage IV patients without mutations (P = .04). In addition, we detected a NRAS(Q61K) mutation in the CTCL cell line Hut78. Knockdown of NRAS by siRNA induced apoptosis in mutant Hut78 cells but not in CTCL cell lines lacking RAS mutations. The NRAS(Q61K) mutation sensitized Hut78 cells toward growth inhibition by the MEK inhibitors U0126, AZD6244, and PD0325901. Furthermore, we found that MEK inhibitors exclusively induce apoptosis in Hut78 cells. Taken together, we conclude that RAS mutations are rare events at a late stage of CTCL, and our preclinical results suggest that such late-stage patients profit from MEK inhibitors.

Inhibition of NF-κB induces a switch from CD95L-dependent to CD95L-independent and JNK-mediated apoptosis in T cells.

NF-κB is a crucial transcription factor regulating apoptosis sensitivity and resistance. It has been shown that inhibition of NF-κB in T lymphocytes leads to sensitization towards apoptosis. The underlying molecular mechanism is not entirely understood. Therefore, we investigated T cell receptor (TCR) stimulated apoptosis in T cells in which NF-κB activity is blocked by an inhibitor or IκBα overexpression. We show that enhanced apoptosis upon TCR stimulation is caspase- and JNK-dependent, but independent of the CD95/CD95L system. Generation of reactive oxygen species (ROS) induced sustained JNK phosphorylation by inactivation of MAP kinase phosphatase 7 (MKP7). Sustained JNK activation causes upregulation of the pro-apototic protein BIM. Thus, inhibition of NF-κB causes a switch from classical activation-induced cell death (AICD) to CD95L-independent apoptosis.

Inhibition of constitutively activated nuclear factor-kappaB induces reactive oxygen species- and iron-dependent cell death in cutaneous T-cell lymphoma.

Aberrant signaling of the nuclear facotr (NF-kappaB) pathway has been identified as a mediator of survival and apoptosis resistance in leukemias and lymphomas. Here, we report that cell death of cutaneous T-cell lymphoma cell lines induced by inhibition of the NF-kappaB pathway is independent of caspases or classic death receptors. We found that free intracellular iron and reactive oxygen species (ROS) are the main mediators of this cell death. Antioxidants such as N-Acetyl-l-cysteine and glutathione or the iron chelator desferrioxamine effectively block cell death in cutaneous T-cell lymphoma cell lines or primary T cells from Sézary patients. We show that inhibition of constitutively active NF-kappaB causes down-regulation of ferritin heavy chain (FHC) that leads to an increase of free intracellular iron, which, in turn, induces massive generation of ROS. Furthermore, direct down-regulation of FHC by siRNA caused a ROS-dependent cell death. Finally, high concentrations of ROS induce cell death of malignant T cells. In contrast, T cells isolated from healthy donors do not display down-regulation of FHC and, therefore, do not show an increase in iron and cell death upon NF-kappaB inhibition. In addition, in a murine T-cell lymphoma model, we show that inhibition of NF-kappaB and subsequent down-regulation of FHC significantly delays tumor growth in vivo. Thus, our results promote FHC as a potential target for effective therapy in lymphomas with aberrant NF-kappaB signaling.

Nonperturbative calculation of born-infeld effects on the schrödinger spectrum of the hydrogen atom.

We present the first nonperturbative calculations of the nonrelativistic hydrogen spectrum as predicted by first-quantized nonlinear Maxwell-Born-Infeld electrodynamics with point charges. Judged against empirical data our results significantly restrict the range of viable values of the new electromagnetic constant beta introduced by Born. We assess Born's own proposal for the value of beta.

Negative specific heat of a magnetically self-confined plasma torus.

It is shown that the thermodynamic maximum-entropy principle predicts negative specific heat for a stationary, magnetically self-confined current-carrying plasma torus. Implications for the magnetic self-confinement of fusion plasma are considered.