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In this work, phytochemical analysis on different extracts of Roccella tinctoria DC. was reported using different techniques with respect to the past. Twenty volatile and three non-volatile compounds were identified, some of which were found in this species for the first time. The methanolic extracts and their non-volatile components were then evaluated for their antitumor effects in cancerous A549 and Mz-ChA-1 cells and for their tolerability in non-cancerous BEAS-2B and H69 cells, showing IC 50 values from 94.6 µg/mL to 416.4 µg/mL, in general. The same extracts and compounds were also tested for their antifungal effects in Candida albicans, with only compound 2 being active, with an MIC 50 value of 87 µg/mL. In addition, they were tested for their anti- Candida adhesion activity, anti- Candida biofilm formation, and anti- Candida mature biofilm inhibition, with efficacy percentages generally above 50% but not for all of them. Lastly, the DF3 extract and compounds 1 - 2 were tested in vivo according to the Galleria mellonella survival assay, showing positive mortality rates above 50% at different concentrations. All these biological assays were conducted on this species for the first time. Comparisons with other lichens and compounds were also presented and discussed.

Taking into account the huge epidemiologic impact of lung cancer (in 2020, lung cancer accounted for 2,206,771 of the cases and for 1,796,144 of the cancer-related deaths, representing the second most common cancer in female patients, the most common cancer in male patients, and the second most common cancer in male and female patients) and the current lack of recommendations in terms of prognostic factors for patients selection and management, this article aims to provide an overview of the current landscape in terms of currently available immunotherapy treatments and the most promising assessed prognostic biomarkers, highlighting the current state-of-the-art and hinting at future challenges.

Vinca sardoa (Stearn) Pignatti, known as Sardinian periwinkle, is widely diffused in Sardinia (Italy). This species contains indole alkaloids, which are known to have a great variety of biological activities. This study investigated the antileukemic activity against a B lymphoblast cell line (SUP-B15) of V. sardoa alkaloid-rich extracts obtained from plants grown in Italy, in Iglesias (Sardinia) and Rome (Latium). All the extracts showed a good capacity to induce reductions in cell proliferation of up to 50% at the tested concentrations (1-15 µg/mL). Moreover, none of the extracts showed cytotoxicity on normal cells at all the studied concentrations.

RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib have revolutionized the landscape of RET-positive (RET+) advanced non-small cell lung cancer (NSCLC) treatment, thanks to their efficacy and safety profiles. This class of medications currently represents the standard of care for both naïve and patients that have not received selective RET-TKIs in the first-line setting. However, we presently lack a satisfactory understanding of resistance mechanism developing after selective RET-TKIs usage, as well as a specific treatment for patients progressing on selpercatinib or pralsetinib. Chemotherapy ± immunotherapy is considered as a recommended subsequent second-line regimen in these patients. Therefore, it is of paramount importance to better define and understand the resistance mechanisms triggered by RET-TKIs. With this in mind, the present review article has been conceived to provide a comprehensive overview about RET+ advanced NSCLC, both from a therapeutic and molecular point of view. Besides comparing the clinical outcome achieved in RET+ advanced NSCLC patients after multikinase inhibitors (MKIs) and/or RET-selective TKIs' administration, we focused on the molecular mechanisms accountable for their long-term resistance. Finally, a critical perspective on many of today's most debated issues and concerns is provided, with the purpose of shaping the possible pharmacological approaches for tomorrow's therapies.

The synthesis and characterization of two tritopic ligands containing a 2,2':6',2″-terpyridine (tpy) metal binding domain and either a 3,2':6',3″- or a 4,2':6',4″-tpy domain are detailed. The synthetic routes to these ligands involved the [Pd(dppf)Cl 2 ]-catalyzed coupling of a boronic ester-functionalized 2,2':6',2″-tpy with bromo-derivatives of 3,2':6',3″-tpy or 4,2':6',4″-tpy. The 2,2':6',2″-tpy domains of the tritopic ligands preferentially bind Fe 2+ in reactions with iron(II) salts leading to the formation of two homoleptic iron(II) complexes containing two peripheral 3,2':6',3″-tpy or 4,2':6',4″-tpy metal-binding sites, respectively. These iron(II) complexes are potentially tetratopic ligands and represent expanded versions of tetra(pyridin-4-yl)pyrazine.

Lung cancer is the leading cause of cancer-related death worldwide. Since prognosis of early-stage non-small cell lung cancer (NSCLC) remains dismal for common relapses after curative surgery, considerable efforts are currently focused on bringing immunotherapy into neoadjuvant and adjuvant settings. Previously, perioperative chemotherapy showed only a modest but significative improvement in overall survival. The presence of broad tumor neoantigens load at primary tumor prior to surgery as well as the known immunosuppressive status following resection represent the main rationale for immunotherapy in early disease. Several trials have been conducted in recent years, leading to atezolizumab and nivolumab approval in the adjuvant and neoadjuvant setting, respectively, and perioperative immunotherapy in NSCLC remains a field of active clinical and preclinical investigation. Unanswered questions in perioperative therapy in NSCLC include the optimal sequence and timing of chemotherapy and immunotherapy, the potential of combination strategies, the role of predictive biomarkers for patient selection and the choice of useful endpoints in clinical investigation.

Agropyron repens (L.) P. Beauv. (couch grass) is a world-wide infesting rhizomatous plant with pharmacological applications. Chemical research is focused on its allelopathic and anti-inflammatory components, which are mainly present in the essential oil. Conversely, the aqueous extracts have been sparingly investigated, although the herbal tea is by far the most used formulation. To fill the gap, the metabolic profile of Agropyron repens rhizome herbal tea was investigated by electrospray ionization (ESI) tandem-mass spectrometry (MS/MS); the phenolic profile was investigated by HPLC-PDA-ESI-MS/MS. ESI-MS fingerprinting was provided, evidencing diagnostic ions for saccharides, organic acids and amino acids. The HPLC-PDA-ESI-MS/MS analysis evidenced at least 20 characteristic phenolic compounds, the most representative being caffeoyl and feruloyl quinic esters, followed by coumaric, caffeic and ferulic acids, and hesperidin among flavonoids. In addition, the essential amino acid tryptophan was identified for the first time. The results suggest new perspectives of applications for Agropyron repens rhizome.

Imidazolium-based dicationic ionic liquids (DILs) are gaining considerable space in the field of organocatalysis mainly due to the opportunities in offering new possible applicable structural variations. In addition to the well-known variables which made the ionic liquids (ILs) famous as the type of cation and anion used, the nature of the molecular spacer moiety turns out a further possibility to improve some physicochemical properties, for example, solubility, acidity, electrochemical behavior, and so on. For this reason, this class of ionic liquids has been considered as possible competitors to their corresponding monocationic salts in replacing common catalysts in organic synthesis, particularly in cases in which their bidentate nature could positively affect the catalytic activity. This mini-review is intended to highlight the progress carried out in the last six years in the field of organocatalysis, including DILs as such and as hybrids with polymers, nanomaterials, and composites.

Coordination networks formed between Co(NCS) 2 and 4'-substituted-[1,1'-biphenyl]-4-yl-3,2':6',3"-terpyridines in which the 4'-group is Me ( 1 ), H ( 2 ), F ( 3 ), Cl ( 4 ) or Br ( 5 ) are reported. [Co( 1 ) 2 (NCS) 2 ] n ·4.5 n CHCl 3 , [Co( 2 ) 2 (NCS) 2 ] n ·4.3 n CHCl 3 , [Co( 3 ) 2 (NCS) 2 ] n ·4 n CHCl 3 , [Co( 4 ) 2 (NCS) 2 ] n , and [Co( 5 ) 2 (NCS) 2 ] n · n CHCl 3 are 2D-networks directed by 4-connecting cobalt nodes. Changes in the conformation of the 3,2':6',3"-tpy unit coupled with the different peripheral substituents lead to three structure types. In [Co( 1 ) 2 (NCS) 2 ] n ·4.5 n CHCl 3 , [Co( 2 ) 2 (NCS) 2 ] n ·4.3 n CHCl 3 , [Co( 3 ) 2 (NCS) 2 ] n ·4 n CHCl 3 , cone-like arrangements of [1,1'-biphenyl]-4-yl units pack through pyridine…arene π-stacking, whereas Cl…π interactions are dominant in the packing in [Co( 4 ) 2 (NCS) 2 ] n . The introduction of the Br substituent in ligand 5 switches off both face-to-face π-stacking and halogen…π-interactions, and the packing interactions are more subtly controlled. Assemblies with organic linkers 1 - 3 are structurally similar and the lattice accommodates CHCl 3 molecules in distinct cavities; thermogravimetric analysis confirmed that half the solvent in [Co( 3 ) 2 (NCS) 2 ] n ·4 n CHCl 3 can be reversibly removed.

The etiology of human asthenozoospermia is multifactorial. The need to unveil molecular mechanisms underlying this state of infertility is, thus, impelling. Circular RNAs (circRNAs) are involved in microRNA (miRNA) inhibition by a sponge activity to protect mRNA targets. All together they form the competitive endogenous RNA network (ceRNET). Recently, we have identified differentially expressed circRNAs (DE-circRNAs) in normozoospermic and asthenozoospermic patients, associated with high-quality (A-spermatozoa) and low-quality (B-spermatozoa) sperm. Here, we carried out a differential analysis of CRISP2 , CATSPER1 and PATE1 mRNA expression in good quality (A-spermatozoa) and low quality (B-spermatozoa) sperm fractions collected from both normozoospermic volunteers and asthenozoospermic patients. These sperm fractions are usually separated on the basis of morphology and motility parameters by a density gradient centrifugation. B-spermatozoa showed low levels of mRNAs. Thus, we identified the possible ceRNET responsible for regulating their expression by focusing on circTRIM2, circEPS15 and circRERE. With the idea that motility perturbations could be rooted in quantitative changes of transcripts in sperm, we evaluated circRNA and mRNA modulation in A-spermatozoa and B-spermatozoa after an oral amino acid supplementation known to improve sperm motility. The profiles of CRISP2, CATSPER1 and PATE1 proteins in the same fractions of sperm well matched with the transcript levels. Our data may strengthen the role of circRNAs in asthenozoospermia and shed light on the molecular pathways linked to sperm motility regulation.

The preparation and characterization of the isomers rac -4'-(4-butan-2-yloxyphenyl)-3,2':6',3″-terpyridine ( rac - 2 ), 4'-(2-methylpropoxyphenyl)-3,2':6',3″-terpyridine ( 3 ) and 4'-( tert -butoxyphenyl)-3,2':6',3″-terpyridine ( 4 ) are reported. The compounds react with Co(NCS) 2 under conditions of crystal growth at room temperature to give single crystals of [{Co( rac - 2 ) 2 (NCS) 2 }·CHCl 3 ] n , [Co( 3 ) 2 (NCS) 2 ] n and [{Co( 4 ) 2 (NCS) 2 }·CHCl 3 ] n which possess (4,4) networks, with the Co centers acting as 4-connecting nodes. Powder X-ray diffraction (PXRD) was used to confirm that the crystals chosen for single crystal X-ray diffraction were representative of the bulk samples. The detailed structures of the three networks have been compared with that of the previously reported [{Co( 1 ) 2 (NCS) 2 }·4CHCl 3 ] n in which 1 is 4'-(butoxyphenyl)-3,2':6',3″-terpyridine. Whereas the switch from 1 with the straight-chain butoxy substituent to rac - 2 , 3 and 4 with branched chains causes significant structural perturbation, changes in the spatial properties of the branched substituents are accommodated with subtle conformational changes in the 3,2':6',3″-tpy domain.

Background: The Anaplastic Lymphoma Kinase (ALK) gene is known to be affected by several genetic alterations, such as rearrangement, amplification and point mutation. The main goal of this study was to comprehensively analyze ALK amplification ( ALK -A) and ALK gene copy number gain ( ALK-CNG ) in a large cohort of non-small-cell lung cancer (NSCLC) patients in order to evaluate the effects on mRNA and protein expression. Methods: ALK locus number status was evaluated in 578 NSCLC cases by fluorescence in situ hybridization (FISH). In addition, ALK immunohistochemistry and ALK mRNA in situ hybridization were performed. Results: Out of 578 cases, 17 cases showed ALK -A. In addition, 14 cases presented AL K-CNG and 72 cases presented chromosome 2 polyploidy. None of those carrying ALK -A and -CNG showed either ALK immunohistochemical expression or ALK mRNA expression through in situ hybridization. We observed a high frequency of extra copies of the ALK gene. Conclusions : Our findings demonstrated that ALK -A is not involved in mRNA production and consequently is not involved in protein production; these findings support the hypothesis that ALK -A might not play a role in the pathogenesis of NSCLC, underlining the absence of a specific clinical application.

The preparation and characterization of 4'-(4- n -octyloxyphenyl)-3,2':6',3″-terpyridine ( 8 ) and 4'-(4- n -nonyloxyphenyl)-3,2':6',3″-terpyridine ( 9 ) are reported. The single crystal structures of 4'-(4- n -hexyloxyphenyl)-3,2':6',3″-terpyridine ( 6 ), 4'-(4- n -heptyloxyphenyl)-3,2':6',3″-terpyridine ( 7 ), and compounds 8 and 9 have been determined. The conformation of the 3,2':6',3″-tpy unit is trans , trans in 6 and 7 , but switches to cis , trans in 8 and 9 . This is associated with significant changes in the packing interactions with a more dominant role for van der Waals interactions between adjacent n -alkyloxy chains and C-H methylene ... π interactions in 8 and 9 . The solid-state structures of 6 and 7 with the n -hexyloxy and n -heptyloxy chains feature interwoven sheets of supramolecular assemblies of molecules, with pairs of n -alkyloxy chains threaded through cavities in an adjacent sheet.

Estrogen receptors (ERα and ERβ) are ligand-activated transcription factors that play different roles in gene regulation and show both overlapping and specific tissue distribution patterns. ERβ, contrary to the oncogenic ERα, has been shown to act as an oncosuppressor in several instances. However, while the tumor-promoting actions of ERα are well-known, the exact role of ERβ in carcinogenesis and tumor progression is not yet fully understood. Indeed, to date, highly variable and even opposite effects have been ascribed to ERβ in cancer, including for example both proliferative and growth-inhibitory actions. Recently ERβ has been proposed as a potential target for cancer therapy, since it is expressed in a variety of breast cancers (BCs), including triple-negative ones (TNBCs). Because of the dependence of TNBCs on active cellular signaling, numerous studies have attempted to unravel the mechanism(s) behind ERβ-regulated gene expression programs but the scenario has not been fully revealed. We comprehensively reviewed the current state of knowledge concerning ERβ role in TNBC biology, focusing on the different signaling pathways and cellular processes regulated by this transcription factor, as they could be useful in identifying new diagnostic and therapeutic approaches for TNBC.

The synthesis and characterization of 4'-(4- n -propoxyphenyl)-3,2':6',3″-terpyridine is described. Five 2D-coordination networks have been isolated by crystal growth at room temperature from reactions of Co(NCS) 2 with 4'-(4- n -alkyloxyphenyl)-3,2':6',3″-terpyridines in which the n -alkyl group is ethyl, n -propyl, n -butyl, n -pentyl and n -hexyl in ligands 2 - 6 , respectively. The single-crystal structures of [{Co( 2 ) 2 (NCS) 2 } . 0.6CHCl 3 ] n , [{Co( 3 ) 2 (NCS) 2 } . 4CHCl 3 . 0.25H 2 O] n , [{Co( 4 ) 2 (NCS) 2 } . 4CHCl 3 ] n , [Co 2 ( 5 ) 4 (NCS) 4 ] n and [Co( 6 ) 2 (NCS) 2 ] n have been determined, and powder X-ray diffraction has demonstrated that the single-crystal structures are representative of the bulk materials. Each compound possesses a (4,4) net with Co centres as 4-connecting nodes. For the assemblies containing 2 , 3 and 4 , the (4,4) net comprises two geometrically different rhombuses, and the nets pack in an ABAB... arrangement with cone-like arrangements of n -alkyloxyphenyl groups being accommodated in a similar unit in an adjacent net. An increase in the n -alkyloxy chain length has two consequences: there is a change in the conformation of the 3,2':6',3″-tpy metal-binding domain, and the (4,4) net comprises identical rhombuses. Similarities and differences between the assemblies with ligands 2 - 6 and the previously reported [{Co( 1 ) 2 (NCS) 2 } . 3MeOH] n and [{Co( 1 ) 2 (NCS) 2 } . 2.2CHCl 3 ] n in which 1 is 4'-(4-methoxyphenyl)-3,2':6',3″-terpyridine are discussed. The results demonstrate the effects of combining a variable chain length in the 4'-(4- n -alkyloxyphenyl) substituents of 3,2':6',3″-tpy and a conformationally flexible 3,2':6',3″-tpy metal-binding domain.

Five coordination polymers formed from combinations of copper(II) acetate and 4'-(4-alkyloxyphenyl)-3,2':6',3''-terpyridines with methoxy ( 1 ), n -butoxy ( 2 ), n -pentyloxy ( 3 ) and n -heptyloxy ( 4 ) substituents are reported. Reaction of 1 with Cu(OAc) 2 ∙H 2 O leads to the 1D-polymer [Cu 2 (μ-OAc) 4 ( 1 )] n in which {Cu 2 (-OAc) 4 } paddle-wheel units are connected by ligands 1 , or [{Cu 4 (μ 3 -OH) 2 (μ-OAc) 2 (μ 3 -OAc) 2 (AcO-κO) 2 ( 1 ) 2 } . 2MeOH] n in which centrosymmetric tetranuclear clusters link pairs of ligands 1 to give a double-stranded 1D-polymer. Layering solutions of Cu(OAc) 2 ∙H 2 O (in MeOH) over 2 , 3 or 4 (in CHCl 3 ) leads to the assembly of the 1D-polymers [2{Cu 2 (μ-OAc) 4 ( 2 )} . 1.25MeOH] n , [Cu 2 (μ-OAc) 4 ( 3 )] n and [{Cu 2 (μ-OAc) 4 ( 4 )} . 0.2CHCl 3 ] n . In all compounds, the 3,2':6',3''-tpy unit coordinates only through the outer pyridine rings, but the conformation of the 3,2':6',3''-tpy responds to changes in the length of the alkyloxy tails leading to changes in the conformation of the polymer backbone and in the packing of the chains in the crystal lattice in the chains featuring {Cu 2 (-OAc) 4 } paddle-wheel linkers., Competing Interests: The authors declare no conflict of interest.

PIWI-like (PIWIL) proteins and small non-coding piRNAs, involved in genome regulation in germline cells, are found aberrantly expressed in human tumors. Gene expression data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the European Genome-Phenome Archive (EGA) indicate that the PIWIL1 gene is ectopically activated in a significant fraction of colorectal cancers (CRCs), where this is accompanied by promoter demethylation, together with germline factors required for piRNA production. Starting from this observation, the PIWIL/piRNA pathway was studied in detail in COLO 205 CRC cells, which express significant levels of this protein, to investigate role and significance of ectopic PIWIL1 expression in human tumors. RNA sequencing and cell and computational biology led to the demonstration that PIWIL1 localizes in a nuage-like structure located in the perinuclear region of the cell and that a significant fraction of the piRNAs expressed in these cells are methylated, and, therefore, present in an active form. This was further supported by RNA immunoprecipitation, which revealed how several piRNAs can be found loaded into PIWIL1 to form complexes also comprising their target mRNAs. The mature transcripts associated with the PIWIL-piRNA complex encode key regulatory proteins involved in the molecular mechanisms sustaining colorectal carcinogenesis, suggesting that the PIWI/piRNA pathway may actively contribute to the establishment and/or maintenance of clinico-pathological features of CRCs.

Manipulation of the immune response is a game changer in lung cancer treatment, revolutionizing management. PD1 and CTLA4 are dynamically expressed on different T cell subsets that can either disrupt or sustain tumor growth. Monoclonal antibodies (MoAbs) against PD1/PDL1 and CTLA4 have shown that inhibitory signals can be impaired, blocking T cell activation and function. MoAbs, used as both single-agents or in combination with standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC), have exhibited advantages in terms of overall survival and response rate; nivolumab, pembrolizumab, atezolizumab and more recently, durvalumab, have already been approved for lung cancer treatment and more compounds are in the pipeline. A better understanding of signaling elicited by these antibodies on T cell subsets, as well as identification of biological determinants of sensitivity, resistance and correlates of efficacy, will help to define the mechanisms of antitumor responses. In addition, the relevance of T regulatory cells (Treg) involved in immune responses in cancer is attracting increasing interest. A major challenge for future research is to understand why a durable response to immune checkpoint inhibitors (ICIs) occurs only in subsets of patients and the mechanisms of resistance after an initial response. This review will explore current understanding and future direction of research on ICI treatment in lung cancer and the impact of tumor immune microenvironment n influencing clinical responses.

The synthesis and characterization of 4'-(4-methoxyphenyl)-3,2':6',3″-terpyridine ( 2 ) (IUPAC PIN 2 4 -(4-methoxyphenyl)-1 2 ,2 2 :2 6 ,3 2 -terpyridine) are described, and its coordination behaviour with cobalt(II) thiocyanate has been investigated. In a series of experiments, crystals were grown at room temperature by layering a MeOH solution of Co(NCS) 2 over a CHCl 3 solution of 2 using 1:1, 1:2 or 2:1 molar ratios of metal salt-to-ligand. Crystals harvested within 2-3 weeks proved to be the 1D-coordination polymer [Co( 2 )(NCS) 2 (MeOH) 2 ] n and powder X-ray diffraction (PXRD) confirmed that the crystals selected for single-crystal X-ray diffraction were representative of the bulk samples. Longer crystallization times with a Co(NCS) 2 to 2 molar ratio of 1:1 yielded crystals of [Co( 2 )(NCS) 2 (MeOH) 2 ] n (1D-chain) and the pseudopolymorphs [{Co( 2 ) 2 (NCS) 2 }·3MeOH] n and [{Co( 2 ) 2 (NCS) 2 }·2.2CHCl 3 ] n ((4,4)-nets), each type of crystal originating from a different zone in the crystallization tube. PXRD for this last experiment confirmed that the dominant product in the bulk sample was the 1D-coordination polymer.

The preparation of 2 4 -functionalized 1 2 ,2 2 :2 6 ,3 2 -terpyridines (4'-functionalized 3,2:6',3''-terpyridines) by the reaction of three 4-alkoxybenzaldehydes with 3-acetylpyridine and ammonia was investigated; under identical reaction conditions, two (R = n C 4 H 9 , C 2 H 5 ) gave the expected products whereas a third (R = n C 3 H 7 ) gave only a cyclohexanol derivative derived from the condensation of three molecules of 3-acetylpyridine with two of 4-( n -propoxy)benzaldehyde. A comprehensive survey of ''unexpected'' products from reactions of ArCOCH 3 derivatives with aromatic aldehydes is presented. Three different types of alternative product are identified., Competing Interests: The authors declare no conflict of interest.

The therapeutic scenario for elderly patients with advanced NSCLC has been limited to radiotherapy and chemotherapy. Recently, a novel therapeutic approach based on targeting the immune-checkpoints has showed noteworthy results in advanced NSCLC. PD1/PD-L1 pathway is co-opted by tumor cells through the expression of PD-L1 on the tumor cell surface and on cells within the microenvironment, leading to suppression of anti-tumor cytolytic T-cell activity by the tumor. The success of immune-checkpoints inhibitors in clinical trials led to rapid approval by the FDA and EMA. Currently, data regarding efficacy and safety of ICIs in older subjects is limited by the poor number of elderly recruited in clinical trials. Careful assessment and management of comorbidities is essential to achieve better outcomes and limit the immune related adverse events in elderly NSCLC patients.