Ion Channel Involvement in Tumor Drug Resistance

Over 90% of deaths in cancer patients are attributed to tumor drug resistance. Resistance to therapeutic agents can be due to an innate property of cancer cells or can be acquired during chemotherapy. In recent years, it has become increasingly clear that regulation of membrane ion channels is an important mechanism in the development of chemoresistance. Here, we review the contribution of ion channels in drug resistance of various types of cancers, evaluating their potential in clinical management. Several molecular mechanisms have been proposed, including evasion of apoptosis, cell cycle arrest, decreased drug accumulation in cancer cells, and activation of alternative escape pathways such as autophagy. Each of these mechanisms leads to a reduction of the therapeutic efficacy of administered drugs, causing more difficulty in cancer treatment. Thus, targeting ion channels might represent a good option for adjuvant therapies in order to counteract chemo-resistance development

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

Skeletal muscle ion channelopathies (SMICs) are a large heterogeneous group of rare genetic disorders caused by mutations in genes encoding ion channel subunits in the skeletal muscle mainly characterized by myotonia or periodic paralysis, potentially resulting in long-term disabilities. However, with the development of new molecular technologies, new genes and new phenotypes, including progressive myopathies, have been recently discovered, markedly increasing the complexity in the field. In this regard, new advances in SMICs show a less conventional role of ion channels in muscle cell division, proliferation, differentiation, and survival. Hence, SMICs represent an expanding and exciting field. Here, we review current knowledge of SMICs, with a description of their clinical phenotypes, cellular and molecular pathomechanisms, and available treatments

Target mutation-driven drug discovery

In the era of precision medicine, genetics is becoming a key factor for the choice of therapies. For decades, it has been intuitively thought that variability in drug response relies, at least partly, on gene variants that may affect the pharmacokinetics and pharmacodynamics of drugs. The most considerable evidences regard polymorphisms in genes encoding enzymes and carriers involved in the ADME processes. Nowadays, more attention should be paid to genetic variations in drug targets, especially in cancer and rare diseases

An Insight into Chemistry and Structure of Colloidal 2D-WS2 Nanoflakes: Combined XPS and XRD Study

The surface and structural characterization techniques of three atom-thick bi-dimensional 2D-WS2 colloidal nanocrystals cross the limit of bulk investigation, offering the possibility of simultaneous phase identification, structural-to-morphological evaluation, and surface chemical description. In the present study, we report a rational understanding based on X-ray photoelectron spectroscopy (XPS) and structural inspection of two kinds of dimensionally controllable 2D-WS2 colloidal nanoflakes (NFLs) generated with a surfactant assisted non-hydrolytic route. The qualitative and quantitative determination of 1T’ and 2H phases based on W 4f XPS signal components, together with the presence of two kinds of sulfur ions, S22− and S2−, based on S 2p signal and related to the formation of WS2 and WOxSy in a mixed oxygen-sulfur environment, are carefully reported and discussed for both nanocrystals breeds. The XPS results are used as an input for detailed X-ray Diffraction (XRD) analysis allowing for a clear discrimination of NFLs crystal habit, and an estimation of the exact number of atomic monolayers composing the 2D-WS2 nanocrystalline samples

Clinical, Molecular, and Functional Characterization of CLCN1 Mutations in Three Families with Recessive Myotonia Congenita

Myotonia congenita (MC) is an inherited muscle disease characterized by impaired muscle relaxation after contraction, resulting in muscle stiffness. Both recessive (Becker's disease) or dominant (Thomsen's disease) MC are caused by mutations in the CLCN1 gene encoding the voltage-dependent chloride ClC-1 channel, which is quite exclusively expressed in skeletal muscle. More than 200 CLCN1 mutations have been associated with MC. We provide herein a detailed clinical, molecular, and functional evaluation of four patients with recessive MC belonging to three different families. Four CLCN1 variants were identified, three of which have never been characterized. The c.244A>G (p.T82A) and c.1357C>T (p.R453W) variants were each associated in compound heterozygosity with c.568GG>TC (p.G190S), for which pathogenicity is already known. The new c.809G>T (p.G270V) variant was found in the homozygous state. Patch-clamp studies of ClC-1 mutants expressed in tsA201 cells confirmed the pathogenicity of p.G270V, which greatly shifts the voltage dependence of channel activation toward positive potentials. Conversely, the mechanisms by which p.T82A and p.R453W cause the disease remained elusive, as the mutated channels behave similarly to WT. The results also suggest that p.G190S does not exert dominant-negative effects on other mutated ClC-1 subunits. Moreover, we performed a RT-PCR quantification of selected ion channels transcripts in muscle biopsies of two patients. The results suggest gene expression alteration of sodium and potassium channel subunits in myotonic muscles; if confirmed, such analysis may pave the way toward a better understanding of disease phenotype and a possible identification of new therapeutic options

Immersive and Non-Immersive Virtual Reality for Pain and Anxiety Management in Pediatric Patients with Hematological or Solid Cancer: A Systematic Review

Invasive and painful procedures, which often induce feelings of anxiety, are necessary components of pediatric cancer treatment, and adequate pain and anxiety management during these treatments is of pivotal importance. In this context, it is widely recognized that a holistic approach, including pharmacological and non-pharmacological modalities, such as distraction techniques, should be the standard of care. Recent evidence suggested the use of virtual reality (VR) as an effective non-pharmacological intervention in pediatrics. Therefore, this systematic review aims to analyze previously published studies on the effectiveness of VR for the management of pain and/or anxiety in children and adolescents with hematological or solid cancer. Medline, SCOPUS, Web of Science, ProQuest, CINAHL, and The Cochrane Central Register of Controlled Trials were used to search for relevant studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Randomized controlled trial, crossover trial, cluster randomized trial, and quasi-experimental studies were included. Thirteen studies, published between 1999 and 2022, that fulfilled the inclusion criteria were included. Regarding the primary outcomes measured, pain was considered in five studies, anxiety in three studies, and the remaining five studies analyzed the effectiveness of VR for both pain and anxiety reduction. Our findings suggested a beneficial effect of VR during painful vascular access procedures. Limited data are available on the reduction of anxiety in children with cancer

Musculoskeletal Features without Ataxia Associated with a Novel de novo Mutation in KCNA1 Impairing the Voltage Sensitivity of Kv1.1 Channel

The KCNA1 gene encodes the subunit of the voltage-gated Kv1.1 potassium channel that critically regulates neuronal excitability in the central and peripheral nervous systems. Mutations in KCNA1 have been classically associated with episodic ataxia type 1 (EA1), a movement disorder triggered by physical and emotional stress. Additional features variably reported in recent years include epilepsy, myokymia, migraine, paroxysmal dyskinesia, hyperthermia, hypomagnesemia, and cataplexy. Interestingly, a few individuals with neuromyotonia, either isolated or associated with skeletal deformities, have been reported carrying variants in the S2–S3 transmembrane segments of Kv1.1 channels in the absence of any other symptoms. Here, we have identified by whole-exome sequencing a novel de novo variant, T268K, in KCNA1 in a boy displaying recurrent episodes of neuromyotonia, muscle hypertrophy, and skeletal deformities. Through functional analysis in heterologous cells and structural modeling, we show that the mutation, located at the extracellular end of the S3 helix, causes deleterious effects, disrupting Kv1.1 function by altering the voltage dependence of activation and kinetics of deactivation, likely due to abnormal interactions with the voltage sensor in the S4 segment. Our study supports previous evidence suggesting that specific residues within the S2 and S3 segments of Kv1.1 result in a distinctive phenotype with predominant musculoskeletal presentation

In-plane Aligned Colloidal 2D WS2 Nanoflakes for Solution- Processable Thin Films with High Planar Conductivity

Two-dimensional transition-metal dichalcolgenides (2D-TMDs) are among the most intriguing materials for next-generation electronic and optoelectronic devices. Albeit still at the embryonic stage, building thin films by manipulating and stacking preformed 2D nanosheets is now emerging as a practical and cost-effective bottom-up paradigm to obtain excellent electrical properties over large areas. Herein, we exploit the ultrathin morphology and outstanding solution stability of 2D WS2 colloidal nanocrystals to make thin films of TMDs assembled on a millimetre scale by a layer-by-layer deposition approach. We found that a room-temperature surface treatment with a superacid, performed with the precise scope of removing the native insulating surfactants, promotes in-plane assembly of the colloidal WS2 nanoflakes into stacks parallel to the substrate, along with healing of sulphur vacancies in the lattice that are detrimental to electrical conductivity. The as-obtained 2D WS2 thin films, characterized by a smooth and compact morphology, feature a high planar conductivity of up to 1 μS, comparable to the values reported for epitaxially grown WS2 monolayers, and enable photocurrent generation upon light irradiation over a wide range of visible to near-infrared frequencie

ClC-1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype-phenotype correlation

Loss-of-function mutations of the skeletal muscle ClC-1 channel cause myotonia congenita with variable phenotypes. Using patch clamp we show that F484L, located in the conducting pore, probably induces mild dominant myotonia by right-shifting the slow gating of ClC-1 channel, without exerting a dominant-negative effect on the wild-type (WT) subunit. Molecular dynamics simulations suggest that F484L affects the slow gate by increasing the frequency and the stability of H-bond formation between E232 in helix F and Y578 in helix R. Three other myotonic ClC-1 mutations are shown to produce distinct effects on channel function: L198P shifts the slow gate to positive potentials, V640G reduces channel activity, while L628P displays a WT-like behaviour (electrophysiology data only). Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function

Ion Channel Involvement in Tumor Drug Resistance

Over 90% of deaths in cancer patients are attributed to tumor drug resistance. Resistance to therapeutic agents can be due to an innate property of cancer cells or can be acquired during chemotherapy. In recent years, it has become increasingly clear that regulation of membrane ion channels is an important mechanism in the development of chemoresistance. Here, we review the contribution of ion channels in drug resistance of various types of cancers, evaluating their potential in clinical management. Several molecular mechanisms have been proposed, including evasion of apoptosis, cell cycle arrest, decreased drug accumulation in cancer cells, and activation of alternative escape pathways such as autophagy. Each of these mechanisms leads to a reduction of the therapeutic efficacy of administered drugs, causing more difficulty in cancer treatment. Thus, targeting ion channels might represent a good option for adjuvant therapies in order to counteract chemoresistance development