Quantifying Variations in Metal-Ligand Cooperative Binding Strength with Cyclic Voltammetry and Redox-Active Ligands.

Metal-ligand cooperativity (MLC), a phenomenon that leverages reactive ligands to promote synergistic reactions with metals, has proven to be a powerful approach to achieving new and unprecedented chemical transformations with metal complexes. While many examples of MLC are known with a wide range of substrates, experimentally quantifying how ligand modifications affect MLC binding strength remains a challenge. Here we describe how cyclic voltammetry (CV) was used to quantify differences in MLC binding strength in a series of square-pyramidal Ru complexes. This method relies on using multifunctional ligands (those capable of both MLC and ligand-centered redox activity) as electrochemical reporters of MLC binding strength. The synthesis and characterization of Ru complexes with three different redox-active tetradentate ligands and two different ancillary phosphines (PPh3 and PCy3) are described. Titration CV studies conducted using BH3·THF with BH3 as a model MLC substrate allowed ΔGMLC to be quantified for each complex. Compared to our base triaryl ligand, increasing π conjugation in the backbone of the redox-active ligand enhanced MLC binding, whereas increasing π conjugation in the flanking groups decreased the MLC binding strength. Structures and spectroscopic data collected for the isolated MLC complexes are also described along with supporting DFT calculations that were used to illuminate electronic factors that likely account for the observed differences in the MLC binding strength. These results demonstrate how redox-active ligands and CV can be used to quantify subtle differences in the MLC binding strength across a series of structurally related complexes with different ligand modifications.

A Promising Thermodynamic Study of Hole Transport Materials to Develop Solar Cells: 1,3-Bis(N-carbazolyl)benzene and 1,4-Bis(diphenylamino)benzene.

The thermochemical study of the 1,3-bis(N-carbazolyl)benzene (NCB) and 1,4-bis(diphenylamino)benzene (DAB) involved the combination of combustion calorimetric (CC) and thermogravimetric techniques. The molar heat capacities over the temperature range of (274.15 to 332.15) K, as well as the melting temperatures and enthalpies of fusion were measured for both compounds by differential scanning calorimetry (DSC). The standard molar enthalpies of formation in the crystalline phase were calculated from the values of combustion energy, which in turn were measured using a semi-micro combustion calorimeter. From the thermogravimetric analysis (TGA), the rate of mass loss as a function of the temperature was measured, which was then correlated with Langmuir's equation to derive the vaporization enthalpies for both compounds. From the combination of experimental thermodynamic parameters, it was possible to derive the enthalpy of formation in the gaseous state of each of the title compounds. This parameter was also estimated from computational studies using the G3MP2B3 composite method. To prove the identity of the compounds, the 1H and 13C spectra were determined by nuclear magnetic resonance (NMR), and the Raman spectra of the study compounds of this work were obtained.

Effective Approach to Render Stable Dynamic Omniphobicity and Icephobicity to Ultrasmooth Metal Surfaces.

Surface modifications for easy removal of liquids and solids from various metal surfaces are much less established than for silicon (Si) or glass substrates. Trimethylsiloxy-terminated polymethylhydrosiloxane (PMHS) is very promising because it can be directly immobilized covalently to a wide variety of metal surfaces by simply heating neat PMHS liquid, resulting in a film showing excellent dynamic omniphobicity. However, such PMHS films are easily degraded by hydrolytic attack in an aqueous environment. In this study, we have successfully improved the hydrolytic stability of the PMHS-covered ultrasmooth metal (Ti, Al, Cr, Ni, and Cu) surfaces by end-capping of the residual Si-H groups of the PMHS films with vinyl-terminated organosilanes, for example, trimethylvinylsilane (TMVS), through a platinum-catalyzed hydrosilylation reaction. The resulting TMVS-capped PMHS film surfaces showed significantly greater stability even after submersion in water for 6 days, with their excellent dynamic dewetting behavior toward water, toluene, n-hexadecane, and ethanol changing little. In addition, they also showed reasonable anti-icing (icephobic) properties with low ice-adhesion strength of less than 50 kPa even after 20 cycles of testing at -15 °C.

Targeted therapy moves to earlier stages of non-small-cell lung cancer: emerging evidence, controversies and future challenges.

Lung cancer continues to be the leading cause of cancer mortality and a serious health problem despite the numerous advances made in the last decade and the rapid advance of research in this field. In recent years, there has been a decrease in mortality from lung cancer coinciding with the approval times of targeted therapy. To date, targeted therapy has been used in the context of advanced disease in clinical practice, with great benefits in survival and quality of life. The next step will be to incorporate targeted therapy into the treatment of earlier stages of non-small-cell lung cancer, and there is already a randomized trial showing a disease-free survival benefit. However, there are many questions that need to be resolved first. In the present review, the authors discuss the findings of published reports and ongoing clinical trials assessing the role of targeted therapies in nonmetastatic disease.

Lay abstract Despite major therapeutic advances over the last decade, lung cancer continues to present the highest mortality rate of all cancers. Precision and personalized therapy directed at specific alterations in the genetic material of the tumor as well as immunotherapy has significantly improved survival in metastatic non-small-cell lung cancer. The next step will be to incorporate precision medicine into the treatment of earlier stages of non-small-cell lung cancer. The recent publication of the results of the ADAURA phase III trial showing a significant improvement in disease-free survival in patients with resected EGFR-mutated non-small-cell lung cancer who received an adjuvant EGFR-directed tyrosine kinase inhibitor called osimertinib has opened the doors to the incorporation of this novel agent into routine clinical practice. However, there are many questions that need to be resolved first. In the present review, the authors discuss the findings of published reports and ongoing clinical trials assessing the role of precision medicine in nonmetastatic disease.

Cambiarenes: Single-Step Synthesis and Selective Zwitterion Binding of a Clip-Shaped Macrocycle with a Redox-Active Core.

A novel macrocyclic host molecule was synthesized that forms in a single step from commercially available starting materials. The core of the macrocycle backbone possesses two quinone rings and, thus, it is redox-active. Host-guest binding involving the clip-shaped cavity indicates selective binding of pyridine N-oxides based on the electron density of and steric bulk around the anionic oxygen.

Influence of Multisite Metal-Ligand Cooperativity on the Redox Activity of Noninnocent N2S2 Ligands.

Metal-ligand cooperativity (MLC) relies on chemically reactive ligands to assist metals with small-molecule binding and activation, and it has facilitated unprecedented examples of catalysis with metal complexes. Despite growing interest in combining ligand-centered chemical and redox reactions for chemical transformations, there are few studies demonstrating how chemically engaging redox active ligands in MLC affects their electrochemical properties when bound to metals. Here we report stepwise changes in the redox activity of model Ru complexes as zero, one, and two BH3 molecules undergo MLC binding with a triaryl noninnocent N2S2 ligand derived from o-phenylenediamine (L1). A similar series of Ru complexes with a diaryl N2S2 ligand with ethylene substituted in place of phenylene (L2) is also described to evaluate the influence of the o-phenylenediamine subunit on redox activity and MLC. Cyclic voltammetry (CV) studies and density functional theory (DFT) calculations show that MLC attenuates ligand-centered redox activity in both series of complexes, but electron transfer is still achieved when only one of the two redox-active sites on the ligands is chemically engaged. The results demonstrate how incorporating more than one multifunctional reactive site could be an effective strategy for maintaining redox noninnocence in ligands that are also chemically reactive and competent for MLC.

The Influence of Redox-Innocent Donor Groups in Tetradentate Ligands Derived from o-Phenylenediamine: Electronic Structure Investigations with Nickel.

The continued development of redox-active ligands requires an understanding as to how ligand modifications and related factors affect the locus of redox activity and spin density in metal complexes. Here we describe the synthesis, characterization, and electronic structure of nickel complexes containing triaryl NNNN (1) and SNNS (2) ligands derived from o-phenylenediamine. The tetradentate ligands in 1 and 2 were investigated and compared to those in metal complexes with compositionally similar ligands to determine how ligand-centered redox properties change when redox-active flanking groups are replaced with redox-innocent NMe2 or SMe. A derivative of 2 in which the phenylene backbone was replaced with ethylene (3) was also prepared to interrogate the importance of o-phenylenediamine for ligand-centered redox activity. Cyclic voltammograms collected for 1 and 2 revealed two fully reversible ligand-centered redox events. Remarkably, several quasi-reversible ligand-centered redox waves were also observed for 3 despite the absence of the o-phenylenediamine subunit. Oxidizing 1 and 2 with silver salts containing different counteranions (BF4-, OTf-, NTf2-) allowed the electrochemically generated complexes to be analyzed as a function of different oxidation states using single-crystal X-ray diffraction (XRD), EPR spectroscopy, and S K-edge X-ray absorption spectroscopy. The experimental data are corroborated by DFT calculations, and together, they reveal how the location of unpaired spin density and electronic structure in singly and doubly oxidized salts of 1 and 2 varies depending on the coordinating ability of the counteranions and exogenous ligands such as pyridine.

Reduction in activity by noxious chemical stimulation is ameliorated by immersion in analgesic drugs in zebrafish.

Research has recently demonstrated that larval zebrafish show similar molecular responses to nociception to those of adults. Our study explored whether unprotected larval zebrafish exhibited altered behaviour after exposure to noxious chemicals and screened a range of analgesic drugs to determine their efficacy to reduce these responses. This approach aimed to validate larval zebrafish as a reliable replacement for adults as well as providing a high-throughput means of analysing behavioural responses. Zebrafish at 5 days post-fertilization were exposed to known noxious stimuli: acetic acid (0.01%, 0.1% and 0.25%) and citric acid (0.1%, 1% and 5%). The behavioural response of each was recorded and analysed using novel tracking software that measures time spent active in 25 larvae at one time. Subsequently, the efficacy of aspirin, lidocaine, morphine and flunixin as analgesics after exposure to 0.1% acetic acid was tested. Larvae exposed to 0.1% and 0.25% acetic acid spent less time active, whereas those exposed to 0.01% acetic acid and 0.1-5% citric acid showed an increase in swimming activity. Administration of 2.5 mg l-1 aspirin, 5 mg l-1 lidocaine and 48 mg l-1 morphine prevented the behavioural changes induced by acetic acid. These results suggest that larvae respond to a noxious challenge in a similar way to adult zebrafish and other vertebrates and that the effect of nociception on activity can be ameliorated by using analgesics. Therefore, adopting larval zebrafish could represent a direct replacement of a protected adult fish with a non-protected form in pain- and nociception-related research.

Effects of Pro-Tex on zebrafish (Danio rerio) larvae, adult common carp (Cyprinus carpio) and adult yellowtail kingfish (Seriola lalandi).

Aquaculture practices bring several stressful events to fish. Stressors not only activate the hypothalamus-pituitary-interrenal-axis, but also evoke cellular stress responses. Up-regulation of heat shock proteins (HSPs) is among the best studied mechanisms of the cellular stress response. An extract of the prickly pear cactus (Opuntia ficus indica), Pro-Tex, a soluble variant of TEX-OE(®), may induce expression of HSPs and reduce negative effects of cellular stress. Pro-Tex therefore is used to ameliorate conditions during stressful aquaculture-related practices. We tested Pro-Tex in zebrafish (Danio rerio), common carp (Cyprinus carpio L.) and yellowtail kingfish (Seriola lalandi) exposed to aquaculture-relevant stressors (thermal stress, net confinement, transport) and assessed its effects on stress physiology. Heat shock produced a mild increase in hsp70 mRNA expression in 5-day-old zebrafish larvae. Pro-Tex increased basal hsp70 mRNA expression, but decreased heat-shock-induced expression of hsp70 mRNA. In carp, Pro-Tex increased plasma cortisol and glucose levels, while it did not affect the mild stress response (increased plasma cortisol and glucose) to net confinement. In gills, and proximal and distal intestine, stress increased hsp70 mRNA expression; in the distal intestine, an additive enhancement of hsp70 mRNA expression by Pro-Tex was seen under stress. In yellowtail kingfish, Pro-Tex reduced the negative physiological effects of transport more efficiently than when fish were sedated with AQUI-S(®). Overall, our data indicate that Pro-Tex has protective effects under high levels of stress only. As Pro-Tex has potential for use in aquaculture, its functioning and impact on health and welfare of fish should be further studied.

Single-fraction stereotactic ablative body radiation therapy for primary and metastasic lung tumor: A new paradigm?

Stereotactic ablative body radiotherapy (SABR) is an effective technique comparable to surgery in terms of local control and efficacy in early stages of non-small cell lung cancer (NSCLC) and pulmonary metastasis. Several fractionation schemes have proven to be safe and effective, including the single fraction (SF) scheme. SF is an option cost-effectiveness, more convenience and comfortable for the patient and flexible in terms of its management combined with systemic treatments. The outbreak of the severe acute respiratory syndrome coronavirus 2 pandemic has driven this not new but underutilized paradigm, recommending this option to minimize patients' visits to hospital. SF SABR already has a long experience, strong evidence and sufficient maturity to reliably evaluate outcomes in peripheral primary NSCLC and there are promising outcomes in pulmonary metastases, making it a valid treatment option; although its use in central locations, synchronous and recurrencies tumors requires more prospective safety and efficacy studies. The SABR radiobiology study, together with the combination with systemic therapies, (targeted therapies and immunotherapy) is a direction of research in both advanced disease and early stages whose future includes SF.

Altered gene expression and ecological divergence in sibling allopolyploids of Dactylorhiza (Orchidaceae).

BACKGROUND: Hybridization and polyploidy are potent forces that have regularly stimulated plant evolution and adaptation. Dactylorhiza majalis s.s., D. traunsteineri s.l. and D. ebudensis are three allopolyploid species of a polyploid complex formed through unidirectional (and, in the first two cases, recurrent) hybridization between the widespread diploids D. fuchsii and D. incarnata. Differing considerably in geographical extent and ecological tolerance, the three allopolyploids together provide a useful system to explore genomic responses to allopolyploidization and reveal their role in adaptation to contrasting environments. RESULTS: Analyses of cDNA-AFLPs show a significant increase in the range of gene expression of these allopolyploid lineages, demonstrating higher potential for phenotypic plasticity than is shown by either parent. Moreover, allopolyploid individuals express significantly more gene variants (including novel alleles) than their parents, providing clear evidence of increased biological complexity following allopolyploidization. More genetic mutations seem to have accumulated in the older D. majalis compared with the younger D. traunsteineri since their respective formation. CONCLUSIONS: Multiple origins of the polyploids contribute to differential patterns of gene expression with a distinct geographic structure. However, several transcripts conserved within each allopolyploid taxon differ between taxa, indicating that habitat preferences shape similar expression patterns in these independently formed tetraploids. Statistical signals separate several transcripts - some of them novel in allopolyploids - that appear correlated with adaptive traits and seem to play a role favouring the persistence of individuals in their native environments. In addition to stabilizing the allopolyploid genome, genetic and epigenetic alterations are key determinants of adaptive success of the new polyploid species after recurrent allopolyploidization events, potentially triggering reproductive isolation between the resulting lineages.

Recent advances in early stage lung cancer.

Treatment of early-stage non-small cell lung cancer has undergone considerable change in recent years. Areas of great interest to researchers include less invasive surgical methods with lower associated morbidity, indications for adjuvant chemotherapy and radiotherapy, the emergence of stereotactic body radiotherapy (SBRT) for peripheral and central or ultracentral tumors, and the probable role of adjuvant immunotherapy following surgery and SBRT, all of which may influence the management of these patients. RELEVANCE FOR PATIENTS: At present, the treatment of early stage non-small cell lung cancer is undergoing changes associated with the evolution of existing treatments and the advent of new treatments.

Management of Resectable Stage III-N2 Non-Small-Cell Lung Cancer (NSCLC) in the Age of Immunotherapy.

Stage III non-small-cell lung cancer (NSCLC) with N2 lymph node involvement is a heterogeneous group with different potential therapeutic approaches. Patients with potentially resectable III-N2 NSCLC are those who are considered to be able to receive a multimodality treatment that includes tumour resection after neoadjuvant therapy. Current treatment for these patients is based on neoadjuvant chemotherapy +/- radiotherapy followed by surgery and subsequent assessment for adjuvant chemotherapy and/or radiotherapy. In addition, some selected III-N2 patients could receive upfront surgery or pathologic N2 incidental involvement can be found a posteriori during analysis of the surgical specimen. The standard treatment for these patients is adjuvant chemotherapy and evaluation for complementary radiotherapy. Despite being a locally advanced stage, the cure rate for these patients continues to be low, with a broad improvement margin. The most immediate hope for improving survival data and curing these patients relies on integrating immunotherapy into perioperative treatment. Immunotherapy based on anti-PD1/PD-L1 immune checkpoint inhibitors is already a standard treatment in stage III unresectable and advanced NSCLC. Data from the first phase II studies in monotherapy neoadjuvant therapy and, in particular, in combination with chemotherapy, are highly promising, with impressive improved and complete pathological response rates. Despite the lack of confirmatory data from phase III trials and long-term survival data, and in spite of various unresolved questions, immunotherapy will soon be incorporated into the armamentarium for treating stage III-N2 NSCLC. In this article, we review all therapeutic approaches to stage III-N2 NSCLC, analysing both completed and ongoing studies that evaluate the addition of immunotherapy with or without chemotherapy and/or radiotherapy.

New challenges in the combination of radiotherapy and immunotherapy in non-small cell lung cancer.

Immunotherapy has represented one of the main medical revolutions of recent decades, and is currently a consolidated treatment for different types of tumors at different stages and scenarios, and is present in a multitude of clinical trials. One of the diseases in which it is most developed is non-small cell lung cancer. The combination of radiotherapy and immunotherapy in cancer in general and lung cancer in particular currently represents one of the main focuses of basic and clinical research in oncology, due to the synergy of this interaction, which can improve tumor response, resulting in improved survival and disease control. In this review we present the biochemical and molecular basis of the interaction between radiotherapy and immunotherapy. We also present the current clinical status of this interaction in each of the stages and cases of non-small cell lung cancer, with the main results obtained in the different studies both in terms of tumor response and survival as well as toxicity. Finally, we mention the main studies underway and the challenges of this interaction in the coming years, including how these treatments should be combined to achieve the greatest efficacy with the fewest possible side effects (dose, type of radiotherapy and drugs, sequence of treatments).

GOECP/SEOR clinical guidelines on radiotherapy for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare tumor with poor prognosis and rising incidence. Palliative care is common in MPM as radical treatment with curative intent is often not possible due to metastasis or extensive locoregional involvement. Numerous therapeutic advances have been made in recent years, including the use of less aggressive surgical techniques associated with lower morbidity and mortality (e.g., pleurectomy/decortication), technological advancements in the field of radiotherapy (intensity-modulated radiotherapy, image-guided radiotherapy, stereotactic body radiotherapy, proton therapy), and developments in systemic therapies (chemotherapy and immunotherapy). These improvements have had as yet only a modest effect on local control and survival. Advances in the management of MPM and standardization of care are hampered by the evidence to date, limited by high heterogeneity among studies and small sample sizes. In this clinical guideline prepared by the oncological group for the study of lung cancer of the Spanish Society of Radiation Oncology, we review clinical, histologic, and therapeutic aspects of MPM, with a particular focus on all aspects relating to radiotherapy, including the current evidence base, associations with chemotherapy and surgery, treatment volumes and planning, technological advances, and reradiation.

Randomized Phase III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small-Cell Lung Cancer (PREMER): A GICOR-GOECP-SEOR Study.

PURPOSE: Radiation dose received by the neural stem cells of the hippocampus during whole-brain radiotherapy has been associated with neurocognitive decline. The key concern using hippocampal avoidance-prophylactic cranial irradiation (HA-PCI) in patients with small-cell lung cancer (SCLC) is the incidence of brain metastasis within the hippocampal avoidance zone. METHODS: This phase III trial enrolled 150 patients with SCLC (71.3% with limited disease) to standard prophylactic cranial irradiation (PCI; 25 Gy in 10 fractions) or HA-PCI. The primary objective was the delayed free recall (DFR) on the Free and Cued Selective Reminding Test (FCSRT) at 3 months; a decrease of 3 points or greater from baseline was considered a decline. Secondary end points included other FCSRT scores, quality of life (QoL), evaluation of the incidence and location of brain metastases, and overall survival (OS). Data were recorded at baseline, and 3, 6, 12, and 24 months after PCI. RESULTS: Participants' baseline characteristics were well balanced between the two groups. The median follow-up time for living patients was 40.4 months. Decline on DFR from baseline to 3 months was lower in the HA-PCI arm (5.8%) compared with the PCI arm (23.5%; odds ratio, 5; 95% CI, 1.57 to 15.86; P = .003). Analysis of all FCSRT scores showed a decline on the total recall (TR; 8.7% v 20.6%) at 3 months; DFR (11.1% v 33.3%), TR (20.3% v 38.9%), and total free recall (14.8% v 31.5%) at 6 months, and TR (14.2% v 47.6%) at 24 months. The incidence of brain metastases, OS, and QoL were not significantly different. CONCLUSION: Sparing the hippocampus during PCI better preserves cognitive function in patients with SCLC. No differences were observed with regard to brain failure, OS, and QoL compared with standard PCI.

Immunotherapy Moves to the Early-Stage Setting in Non-Small Cell Lung Cancer: Emerging Evidence and the Role of Biomarkers.

Despite numerous advances in targeted therapy and immunotherapy in the last decade, lung cancer continues to present the highest mortality rate of all cancers. Targeted therapy based on specific genomic alterations, together with PD-1 and CTLA-4 axis blocking-based immunotherapy, have significantly improved survival in advanced non-small cell lung cancer (NSCLC) and both therapies are now well-established in this clinical setting. However, it is time for immunotherapy to be applied in patients with early-stage disease, which would be an important qualitative leap in the treatment of lung cancer patients with curative intent. Preliminary data from a multitude of studies are highly promising, but therapeutic decision-making should be guided by an understanding of the molecular features of the tumour and host. In the present review, we discuss the most recently published studies and ongoing clinical trials, controversies, future challenges and the role of biomarkers in the selection of best therapeutic options.

GOECP/SEOR clinical recommendations for lung cancer radiotherapy during the COVID-19 pandemic.

The coronavirus disease 2019 crisis has had a major and highly complex impact on the clinical practice of radiation oncology worldwide. Spain is one of the countries hardest hit by the virus, with devastating consequences. There is an urgent need to share experiences and offer guidance on decision-making with regard to the indications and standards for radiation therapy in the treatment of lung cancer. In the present article, the Oncological Group for the Study of Lung Cancer of the Spanish Society of Radiation Oncology reviews the literature and establishes a series of consensus-based recommendations for the treatment of patients with lung cancer in different clinical scenarios during the present pandemic.

Alternative management for gynecological cancer care during the COVID-2019 pandemic: A Latin American survey.

OBJECTIVE: To determine the acceptance rate of treatment alternatives for women with either preinvasive conditions or gynecologic cancers during the COVID-19 pandemic among Latin American gynecological cancer specialists. METHODS: Twelve experts in gynecological cancer designed an electronic survey, according to recommendations from international societies, using an online platform. The survey included 22 questions on five topics: consultation care, preinvasive cervical pathology, and cervical, ovarian, and endometrial cancer. The questionnaire was distributed to 1052 specialists in 14 Latin American countries. A descriptive analysis was carried out using statistical software. RESULTS: A total of 610 responses were received, for an overall response rate of 58.0%. Respondents favored offering teleconsultation as triage for post-cancer treatment follow-up (94.6%), neoadjuvant chemotherapy in advanced stage epithelial ovarian cancer (95.6%), and total hysterectomy with bilateral salpingo-oophorectomy and defining adjuvant treatment with histopathological features in early stage endometrial cancer (85.4%). Other questions showed agreement rates of over 64%, except for review of pathology results in person and use of upfront concurrent chemoradiation for early stage cervical cancer (disagreement 56.4% and 58.9%, respectively). CONCLUSION: Latin American specialists accepted some alternative management strategies for gynecological cancer care during the COVID-19 pandemic, which may reflect the region's particularities. The COVID-19 pandemic led Latin American specialists to accept alternative management strategies for gynecological cancer care, especially regarding surgical decisions.