Tepotinib: Management of Adverse Events in Patients With MET Exon 14 Skipping Non-Small Cell Lung Cancer.

BACKGROUND: Tepotinib, a highly selective, oral, once-daily MET inhibitor, has been approved for treatment of metastatic MET exon 14 skipping non-small cell lung cancer. OBJECTIVES: This article provides nurse-specific recommendations for identification and management of tepotinib adverse events (AEs). METHODS: Guidance on monitoring and proactive/reactive AE management was developed based on published literature and real-world nursing experience. Case studies of VISION trial participants were summarized to illustrate key principles. FINDINGS: Tepotinib AEs are generally mild to moderate and manageable, and can include peripheral edema, hypoalbuminemia, nausea, diarrhea, and creatinine increase. Alongside supportive care, tepotinib interruption and dose reduction is recommended for grade 3 AEs. For peripheral edema, proactive monitoring is crucial, and treatment interruption (including frequent, short treatment holidays) should be considered early. Nursing management of tepotinib AEs includes proactive monitoring, patient education, and interprofessional team coordination.

DNA-Binding Properties of a Novel Crenarchaeal Chromatin-Organizing Protein in Sulfolobus acidocaldarius.

In archaeal microorganisms, the compaction and organization of the chromosome into a dynamic but condensed structure is mediated by diverse chromatin-organizing proteins in a lineage-specific manner. While many archaea employ eukaryotic-type histones for nucleoid organization, this is not the case for the crenarchaeal model species Sulfolobus acidocaldarius and related species in Sulfolobales, in which the organization appears to be mostly reliant on the action of small basic DNA-binding proteins. There is still a lack of a full understanding of the involved proteins and their functioning. Here, a combination of in vitro and in vivo methodologies is used to study the DNA-binding properties of Sul12a, an uncharacterized small basic protein conserved in several Sulfolobales species displaying a winged helix-turn-helix structural motif and annotated as a transcription factor. Genome-wide chromatin immunoprecipitation and target-specific electrophoretic mobility shift assays demonstrate that Sul12a of S. acidocaldarius interacts with DNA in a non-sequence specific manner, while atomic force microscopy imaging of Sul12a-DNA complexes indicate that the protein induces structural effects on the DNA template. Based on these results, and a contrario to its initial annotation, it can be concluded that Sul12a is a novel chromatin-organizing protein.

A European survey on the insights of patients living with metastatic colorectal cancer: the patient journey before, during and after diagnosis - an Eastern European perspective.

BACKGROUND: Despite being highly preventable and treatable if diagnosed early, colorectal cancer (CRC) remains the second leading cause of cancer-related death in Europe. Limited information is available from the patient perspective on the persisting unmet needs of the journey of the patient with CRC. OBJECTIVE: To capture European metastatic CRC (mCRC) patients' insights during the patient journey (prediagnosis; diagnosis; postdiagnosis) through a patient survey. METHODS: In total, 883 patients from 15 European countries participated. Participants were divided into four groups from Hungary, Poland, Serbia and 'other European countries' (n=103, 163, 170 and 447 patients, respectively). RESULTS: General awareness of CRC and its symptoms prediagnosis varied among groups, with patients from Poland recording the lowest levels. Screening practices and attitudes also varied; while more patients from Serbia had been invited to CRC screening (~15%) compared with the other groups, the ones not invited claimed mostly (~20%) that would not have attended if they had been invited. Whereas most patients were diagnosed within a month after the first consultation/positive screening, the percentages varied substantially being lowest among patients in Poland (~30%) and Serbia (~25%). Although CRC-related information provision varied, with most informed patients from Hungary (~90%) and least from Serbia (~50%), all groups requested an easier-to-understand language by the healthcare team. Approximately 50% of patients from Eastern Europe had to wait longer than a month to receive treatment, in contrast to ~30% from other European countries. All groups emphasised the unmet need for support from psychologists and other patients. CONCLUSIONS: Our survey reveals the key aspects of the journey of the patient with mCRC and highlights the areas of similarities and differences between patients with mCRC from Eastern Europe versus those from other European countries as well as among patients from different Eastern European countries, calling for improvement particularly around awareness, screening, treatment availability, communication and support networks.

Defining heat shock response for the thermoacidophilic model crenarchaeon Sulfolobus acidocaldarius.

The crenarchaeon Sulfolobus acidocaldarius, growing optimally at temperatures between 75 and 80 °C, thrives in volcanic hot spring habitats that are typified by large temperature gradients, which impose frequent temperature stresses on the cells. Heat shock response is characterized by an upregulation of heat shock proteins, but similar to most (hyper-)thermophilic archaea, S. acidocaldarius seems to be able to bear supra-optimal temperatures with a restricted repertoire of chaperones. Here, we study the physiological consequences of continuous high-temperature stress and rapid heat shock for S. acidocaldarius. Growth experiments and cell viability assays demonstrate that temperatures of 85 °C and higher result in a decreased growth rate and, when the cells are rapidly subjected to a heat shock, a dynamic increase in mRNA levels of all relevant heat shock proteins and a subset of transcription regulators is observed. When exponentially growing cultures are exposed to a heat shock, the survival tipping point is situated around 90 °C, and the rate of heating determines whether cells are able to cope with this stress or whether the defense mechanism immediately fails, leading to extensive cell death. In conclusion, S. acidocaldarius does not seem to be better equipped to handle sudden supra-optimal temperature stress than mesophilic organisms.

YtrASa, a GntR-Family Transcription Factor, Represses Two Genetic Loci Encoding Membrane Proteins in Sulfolobus acidocaldarius.

In bacteria, the GntR family is a widespread family of transcription factors responsible for the regulation of a myriad of biological processes. In contrast, despite their occurrence in archaea only a little information is available on the function of GntR-like transcription factors in this domain of life. The thermoacidophilic crenarchaeon Sulfolobus acidocaldarius harbors a GntR-like regulator belonging to the YtrA subfamily, encoded as the first gene in an operon with a second gene encoding a putative membrane protein. Here, we present a detailed characterization of this regulator, named YtrASa, with a focus on regulon determination and mechanistic analysis with regards to DNA binding. Genome-wide chromatin immunoprecipitation and transcriptome experiments, the latter employing a ytrA Sa overexpression strain, demonstrate that the regulator acts as a repressor on a very restricted regulon, consisting of only two targets including the operon encoding its own gene and a distinct genetic locus encoding another putative membrane protein. For both targets, a conserved 14-bp semi-palindromic binding motif was delineated that covers the transcriptional start site and that is surrounded by additional half-site motifs. The crystallographic structure of YtrASa was determined, revealing a compact dimeric structure in which the DNA-binding motifs are oriented ideally to enable a specific high-affinity interaction with the core binding motif. This study provides new insights into the functioning of a YtrA-like regulator in the archaeal domain of life.

Transcription Regulators in Archaea: Homologies and Differences with Bacterial Regulators.

The fitness and survival of prokaryotic microorganisms depends on their ability to adequately respond to environmental changes, sudden stress conditions and metabolic shifts. An important mechanism underlying this response is the regulation of gene expression mediated by transcription factors that are responsive to small-molecule ligands or other intracellular signals. Despite constituting a distinct domain of life from bacteria and harboring a eukaryotic-like basal transcription apparatus, it is well established that archaea have similar transcription factors pointing to the existence of shared ancestral proteins and to the occurrence of inter-domain horizontal gene transfer events. However, while global structural features of bacterial and archaeal transcription factors are indeed similar, other characteristics imply that archaeal regulators have undergone independent evolution. Here, we discuss the characteristics of Lrp/AsnC, MarR, ArsR/SmtB and TrmB families of transcription factors, which are the dominant families that constitute the transcription factor repertoire in archaea. We exemplify the evolutionary expansion of these families in archaeal lineages by emphasizing homologies and differences with bacterial counterparts in terms of ligand or signal response, physiological functions and mechanistic principles of regulation. As such, we aim to define future research approaches that enable further characterization of the functions and mechanisms of archaeal transcription factors.

A TetR-family transcription factor regulates fatty acid metabolism in the archaeal model organism Sulfolobus acidocaldarius.

Fatty acid metabolism and its regulation are known to play important roles in bacteria and eukaryotes. By contrast, although certain archaea appear to metabolize fatty acids, the regulation of the underlying pathways in these organisms remains unclear. Here, we show that a TetR-family transcriptional regulator (FadRSa) is involved in regulation of fatty acid metabolism in the crenarchaeon Sulfolobus acidocaldarius. Functional and structural analyses show that FadRSa binds to DNA at semi-palindromic recognition sites in two distinct stoichiometric binding modes depending on the operator sequence. Genome-wide transcriptomic and chromatin immunoprecipitation analyses demonstrate that the protein binds to only four genomic sites, acting as a repressor of a 30-kb gene cluster comprising 23 open reading frames encoding lipases and ß-oxidation enzymes. Fatty acyl-CoA molecules cause dissociation of FadRSa binding by inducing conformational changes in the protein. Our results indicate that, despite its similarity in overall structure to bacterial TetR-family FadR regulators, FadRSa displays a different acyl-CoA binding mode and a distinct regulatory mechanism.

Heat shock response in archaea.

An adequate response to a sudden temperature rise is crucial for cellular fitness and survival. While heat shock response (HSR) is well described in bacteria and eukaryotes, much less information is available for archaea, of which many characterized species are extremophiles thriving in habitats typified by large temperature gradients. Here, we describe known molecular aspects of archaeal heat shock proteins (HSPs) as key components of the protein homeostasis machinery and place this in a phylogenetic perspective with respect to bacterial and eukaryotic HSPs. Particular emphasis is placed on structure-function details of the archaeal thermosome, which is a major element of the HSR and of which subunit composition is altered in response to temperature changes. In contrast with the structural response, it is largely unclear how archaeal cells sense temperature fluctuations and which molecular mechanisms underlie the corresponding regulation. We frame this gap in knowledge by discussing emerging questions related to archaeal HSR and by proposing methodologies to address them. Additionally, as has been shown in bacteria and eukaryotes, HSR is expected to be relevant for the control of physiology and growth in various stress conditions beyond temperature stress. A better understanding of this essential cellular process in archaea will not only provide insights into the evolution of HSR and of its sensing and regulation, but also inspire the development of biotechnological applications, by enabling transfer of archaeal heat shock components to other biological systems and for the engineering of archaea as robust cell factories.

Nintedanib in advanced NSCLC: management of adverse events.

Nintedanib plus docetaxel is approved in the EU for the treatment of patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology after first-line chemotherapy. Nintedanib in combination with docetaxel has a manageable safety profile in adenocarcinoma NSCLC patients. The most frequent adverse events (AEs) associated with nintedanib are gastrointestinal events and elevations in liver enzymes. Most AEs can be managed effectively with supportive treatment or a dose reduction and do not require permanent discontinuation. This article aims to provide practical guidance on management of AEs and how patients should be assessed for AEs prior to initiation and regularly monitored throughout treatment. Patients and their carers can play an important role in recognizing and managing AEs and should be given the relevant information, skills and confidence to achieve this.

Overexpression of the trehalase gene AtTRE1 leads to increased drought stress tolerance in Arabidopsis and is involved in abscisic acid-induced stomatal closure.

Introduction of microbial trehalose biosynthesis enzymes has been reported to enhance abiotic stress resistance in plants but also resulted in undesirable traits. Here, we present an approach for engineering drought stress tolerance by modifying the endogenous trehalase activity in Arabidopsis (Arabidopsis thaliana). AtTRE1 encodes the Arabidopsis trehalase, the only enzyme known in this species to specifically hydrolyze trehalose into glucose. AtTRE1-overexpressing and Attre1 mutant lines were constructed and tested for their performance in drought stress assays. AtTRE1-overexpressing plants had decreased trehalose levels and recovered better after drought stress, whereas Attre1 mutants had elevated trehalose contents and exhibited a drought-susceptible phenotype. Leaf detachment assays showed that Attre1 mutants lose water faster than wild-type plants, whereas AtTRE1-overexpressing plants have a better water-retaining capacity. In vitro studies revealed that abscisic acid-mediated closure of stomata is impaired in Attre1 lines, whereas the AtTRE1 overexpressors are more sensitive toward abscisic acid-dependent stomatal closure. This observation is further supported by the altered leaf temperatures seen in trehalase-modified plantlets during in vivo drought stress studies. Our results show that overexpression of plant trehalase improves drought stress tolerance in Arabidopsis and that trehalase plays a role in the regulation of stomatal closure in the plant drought stress response.

Managing patients with metastatic colorectal cancer on bevacizumab.

Bevacizumab (Avastin) is a humanized monoclonal antibody that inhibits the activity of vascular endothelial growth factor (VEGF), a key molecule controlling tumour blood vessel formation (angiogenesis). By inhibiting VEGF and thus tumour angiogenesis, bevacizumab inhibits tumour growth and survival. In patients with metastatic colorectal cancer (CRC), first-line use of bevacizumab in combination with fluoropyrimidine-based chemotherapy improves outcomes compared with chemotherapy alone. The side-effect profile of bevacizumab does not overlap with that of conventional chemotherapy, and it does not significantly exacerbate chemotherapy-induced adverse events. Specific side-effects of special interest for bevacizumab include hypertension, proteinuria, arterial thromboembolic events, wound-healing complications, bleeding events and gastrointestinal perforation. Oncology nurses are key to early recognition and management of side-effects, in addition to having a key role in patient education, facilitating the optimal use of bevacizumab and thus survival of patients with metastatic CRC.

Anti-tumor necrosis factor treatment restores the gut barrier in Crohn's disease.

OBJECTIVES: A primary defect of the tight junctions and, hence, increased intestinal epithelial permeability has been proposed as a basic pathogenic event in Crohn's disease. Challenge of the mucosal immune system by the commensal gut flora would then result in chronic inflammation. Alternatively, increased permeability could be the result of inflammation. Our aim was to study intestinal permeability in refractory Crohn's disease before and after treatment with monoclonal chimeric antibodies directed against tumor necrosis factor (TNF) to investigate whether the abnormal permeability persists after control of inflammation. METHODS: Twenty-three patients with active Crohn's disease were evaluated before and 4 wk after a single infusion of 5 mg/kg infliximab. Intestinal permeability was studied by measurement of urinary excretion of 51Cr-EDTA after oral intake. RESULTS: The increased permeation of 51Cr-EDTA through the small intestine (1.63% interquartile range [IQR] 1.06-2.07) and the overall permeation (3.27% IQR 2.40-4.38) before therapy decreased significantly after infliximab infusion to values (1.04% IQR 0.74-1.54 and 2.42% IQR 2.03-2.80, respectively) in the range of those found in normal volunteers (1.12% IQR 0.85-1.58 and 2.28% IQR 1.88-2.86, respectively). CONCLUSION: Inhibiting the proinflammatory cytokine tumor necrosis factor dramatically reduces gut inflammation and largely restores the gut barrier in Crohn's disease. Our data confirm the central role of TNF in gut barrier modulation in inflammatory conditions in vivo.