Respiratory Complex I dysfunction in cancer: from a maze of cellular adaptive responses to potential therapeutic strategies

Mitochondria act as key organelles in cellular bioenergetics and biosynthetic processes producing signals that regulate different molecular networks for proliferation and cell death. This ability is also preserved in pathologic contexts such as tumorigenesis, during which bioenergetic changes and metabolic reprogramming confer flexibility favoring cancer cells survival in a hostile microenvironment. Although different studies epitomize mitochondrial dysfunction as a pro-tumorigenic hit, genetic ablation or pharmacological inhibition of respiratory Complex I causing a severe impairment are associated with a low proliferative phenotype. In this scenario, it must be considered that despite the initial delay in growth, cancer cells may become able to resume proliferation exploiting molecular mechanisms to overcome growth arrest. Here we highlight the current knowledge on molecular responses activated by Complex I-defective cancer cells to bypass physiological control systems and to re-adapt their fitness during microenvironment changes. Such adaptive mechanisms could reveal possible novel molecular players in synthetic lethality with Complex I impairment, thus providing new synergistic strategies for mitochondria-based anti-cancer therapy

Strategies for single base gene editing in an immortalized human cell line by CRISPR/Cas9 technology

The use of CRISPR/Cas9 system has rapidly grown in the last years. Here, the optimization of gene editing of a single-nucleotide polymorphism in a human non-malignant somatic cell line of thyrocytes (Nthy-Ori) was described highlighting strategies for overcoming the problems concerning the delivery and off-targets. We employed both lentivirus and chemical lipids as delivery agents and two strategies for creating the double-strand breaks (DSB). The former induced a DSB by a classical Cas9 nuclease (standard strategy), while the second one employed a modified Cas9 creating a single-strand break (SSB). The knock-in was carried out using a single-stranded donor oligonucleotide or the HR410-PA donor vector (HR). The desired cells could be obtained by combining the double nickase system with the HR vector transfected chemically. This result could be due to the type of DSB, likely processed mainly by non-homologous end joining when blunt (standard strategy) and by HR when overhanging (double nickase). Our results showed that the double nickase is suitable for knocking-in the immortalized Nthy-Ori cell line, while the standard CRISPR/Cas9 system is suitable for gene knock-out creating in/del mutations

Variation rs2235503 C > A Within the Promoter of MSLN Affects Transcriptional Rate of Mesothelin and Plasmatic Levels of the Soluble Mesothelin-Related Peptide.

Soluble mesothelin-related peptide (SMRP) is a promising biomarker for malignant pleural mesothelioma (MPM), but several confounding factors can reduce SMRP-based test's accuracy. The identification of these confounders could improve the diagnostic performance of SMRP. In this study, we evaluated the sequence of 1,000 base pairs encompassing the minimal promoter region of the MSLN gene to identify expression quantitative trait loci (eQTL) that can affect SMRP. We assessed the association between four MSLN promoter variants and SMRP levels in a cohort of 72 MPM and 677 non-MPM subjects, and we carried out in vitro assays to investigate their functional role. Our results show that rs2235503 is an eQTL for MSLN associated with increased levels of SMRP in non-MPM subjects. Furthermore, we show that this polymorphic site affects the accuracy of SMRP, highlighting the importance of evaluating the individual's genetic background and giving novel insights to refine SMRP specificity as a diagnostic biomarker

Electrochemotherapy in Vulvar Cancer and Cisplatin Combined with Electroporation. Systematic Review and In Vitro Studies

Electrochemotherapy (ECT) is an emerging treatment for solid tumors and an attractive research field due to its clinical results. This therapy represents an alternative local treatment to the standard ones and is based on the tumor-directed delivery of non-ablative electrical pulses to maximize the action of specific cytotoxic drugs such as cisplatin (CSP) and bleomycin (BLM) and to promote cancer cell death. Nowadays, ECT is mainly recommended as palliative treatment. However, it can be applied to a wide range of superficial cancers, having an impact in preventing or delaying tumor progression and therefore in improving quality of life. In addition, during the natural history of the tumor, early ECT may improve patient outcomes. Our group has extensive clinical and research experience on ECT in vulvar tumors in the palliative setting, with 70% overall response rate. So far, in most studies, ECT was based on BLM. However, the potential of CSP in this setting seems interesting due to some theoretical advantages. The purpose of this report is to: (i) compare the efficacy of CSP and BLM-based ECT through a systematic literature review; (ii) report the results of our studies on CSP-resistant squamous cell tumors cell lines and the possibility to overcome chemoresistance using ECT; (iii) discuss the future ECT role in gynecological tumors and in particular in vulvar carcinoma

An integrative identification guide to the Hydrozoa (Cnidaria) of Bocas del Toro, Panama

This work is the first attempt to assess the biodiversity of the Hydrozoa in the Archipiélago de Bocas del Toro (Panamá, Caribbean Sea) using morphology and molecular taxonomy, and to produce field identification tools to help future identification and monitoring efforts in the area. We sampled, identified, vouchered, and barcoded 112 specimens of Hydrozoa from shallow coastal waters (0–22 m depth) in the Archipiélago de Bocas del Toro. The specimens belong to 70 taxa, of which 53 were identified at the species level, and 17 were identified at the genus or family level. We produced 64 sequences of the large ribosomal subunit of the mitochondrial RNA (mt lsu-rRNA, 16S), the genetic marker generally used for barcoding Hydrozoa. We updated the local checklist that now comprises 118 species, and produced 87 detailed taxon identification tables that display species descriptions augmented with pictures, geographic distribution (worldwide and in Bocas del Toro), GenBank accession numbers for the 16S mitochondrial gene, and a synopsis of the families they belong to

Introducing the Bulletin of Atmospheric Science and Technology

The rapid technological development of the past few decades has allowed for an unprecedented wealth of data about ourselves and our planet. The cost reduction of space platforms, the microelectronic revolution and the nearly exponential increase in computer power have been generating novel opportunities to explore and understand the world around us. Tools and theoretical approaches, capable of putting together all the insights we may possibly gain from all these new streams of data in a multidisciplinary framework, are still being developed. We are hence faced with both a unique challenge and an opportunity to make a significant progress in many scientific fields, first and foremost in the atmospheric and climate sciences. We are pleased to announce here the launch of the Bulletin of Atmospheric Science and Technology (BAST), a new peer-reviewed journal which is meant to bridge this gap in the broad area of the atmospheric sciences. The journal encourages a cross-disciplinary approach with an emphasis on new sensor technologies and systems, combined observational and modeling techniques, innovative numerical methods, data analysis, and retrieval techniques. BAST offers a platform to share new ideas and fresh developments to stimulate research activities focusing on urban, coastal, marine, rural, and mountain environments. Particular attention will be given to cross-disciplinary studies, especially those involving citizens for the collection of crowd-sourced data and those devoted to the characterization of uncertainties and homogenization of methods. BAST aims at connecting weather and climate communities using both observational and modeling approaches, creating a forum hosting discussion and brainstorming activities. The journal also hopes to attract contributions reporting approaches or techniques from other scientific fields that can be applicable to atmospheric sciences, as well as contributions where technological developments are discussed alongside with their scientific and societal impacts. In this sense BAST will provide a new platform to support the technological revolution towards a climate-smart society through the collection and exploitation of big data. The journal will give visibility to international experiments and projects in atmospheric science and technology, illustrating preliminary or consolidated results from these initiatives. Additional fields of interest are : environmental protection; observation, understanding, and modeling of hazardous and extreme events and mitigation of their impacts; development of new sensing tools integrating satellite information with surface or airborne measurements; operation of unmanned and remotely piloted air vehicles equipped with sensors of small size and weight, especially remote sensors, pushing electro-optical-mechanical components towards a continuously increasing miniaturization. Research articles, Review articles, Technical reports, Brief reports, Letters and News are welcome. While keeping the focus of the journal on scientific research, the “Bulletin” format provides appropriate visibility to contributions from the operational side, i.e., meteorological services and private companies developing sensors and products of interest to the atmospheric science and technology community. Below we provide a more detailed description of the topics that will be emphasized and fostered in BAST