1′,1′′-Dimethyl-4′-(naphthalen-1-yl)-1,2,3,4-tetra­hydro­naphthalene-2-spiro-3′-pyrrolidine-2′-spiro-3′′-indoline-1,2′′-dione

In the title compound, C32H28N2O2, the pyrrolidine ring adopts an envelope conformation, whereas the cyclo­hexa­none ring in the tetra­hydro­naphthalene fused-ring system adopts a half-chair conformation. The oxindole ring system is oriented at an angle of 48.2 (1)° with respect to the naphthyl ring system. An intra­molecular C—H⋯O close contact is observed. In the crystal, mol­ecules associate via two C—H⋯O hydrogen bonds, forming R 2 2(14) and R 2 2(10) dimers

Ligand-controlled Regioselective Cu-Catalyzed Trifluoromethylation to Generate Trifluoromethylallenes

“Cu–CF3” species have been used historically for a broad spectrum of nucleophilic trifluoromethylation reactions. Although recent advancements have employed ligands to stabilize and harness the reactivity of this key organometallic intermediate, the ability of a ligand to differentiate a regiochemical outcome of a Cu–CF3-mediated or -catalyzed reaction has not been previously reported. Herein, we report the first example of a Cu-catalyzed trifluoromethylation reaction in which a ligand controls the regiochemical outcome. More specifically, we demonstrate the ability of bipyridyl-derived ligands to control the regioselectivity of the Cu-catalyzed nucleophilic trifluoromethylation reactions of propargyl electrophiles to generate trifluoromethylallenes. This method provides a variety of di-, tri- and tetra-substituted trifluoromethylallenes, which can be further modified to generate complex fluorinated substructures

Immune checkpoint inhibitors: the new frontier in non–small cell lung cancer treatment

Hazem El-Osta, Kamran Shahid, Glenn M Mills, Prakash Peddi Department of Medicine, Division of Hematology-Oncology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Abstract: Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field. Keywords: checkpoint inhibitors, immunotherapy, nivolumab, non-small-cell lung cancer, pembrolizumab, programmed death-1, programmed death ligand-

A prospective study on clinical manifestations of paraphenylene diamine containing hair dye poisoning

Introduction: In the developing countries like ours Pesticide poisoning is one of the leading contributors to this preventable tragedy. Recently, Hair dye poisoning is emerging as an important etiological factor. Hair dye consumption is not an uncommon means of intentional self-harm. Hair dye is available in various forms. It’s cheap and easily available form is Hair dye with chief constituent chemical Para-phenylenediamine (PPD). Aims: To study various clinical manifestations of Paraphenylene diamine containing Hair dye poisoning and to observe the temporal sequence of symptoms, Laboratory profile in the patients and relative frequency of complications and their outcome. Materials and methods: It is Prospective Observational Study done in Medical wards and acute medical care unit. Study done on Clinical presentations, Complications, Laboratory profile, Mortality and Treatment of cases of paraphenylene diamine hair dye ingestion were noted. Patients of alleged hair dye ingestion were taken up for study after the exclusion criteria were ruled out. Results: It was observed that the tendency of poisoning by hair dye was more in females than in males and was more in the age group of 15 – 30 years, as with any other poisoning. The symptoms and signs that were observed in this study are burning pain in mouth / throat / abdomen, vomiting, cervicofacial edema, dysphagia etc. The order of chronology of development of these symptoms was burning pain in mouth / throat / abdomen with vomiting within first 40 – 60 minutes maximum upto 120 minutes, followed by development of cervicofacial edema, dyspnea and dysphagia after few hours. A significant statistical correlation was found to exist between development of AKI and the levels of CPK in blood, rhabdomyolysis. Antihistamines, steroids and maintenance of good hydration along with diuresis form the mainstay of therapy. Conclusion: As the burden of handling hair dye cases has been increasing in this part of the state also, primary care physicians, intensive care physicians and nephrologists need to be aware of its clinical manifestations and management. One should be vigilant of the anticipated complications and be prompt in instituting good supportive management to minimize the morbidity and mortality

Exceptional response to cetuximab monotherapy in a patient with metastatic oropharyngeal squamous cell carcinoma: a molecular insight

Prakash Peddi,1 Bhavna Paryani,2 Amol Takalkar,2 Paige Bundrick,3 John Ponugupati,4 Binu Nair,5 Hazem El-Osta1 1Department of Medicine, Division of Hematology-Oncology, 2Department of Radiology, 3Department of Head and Neck Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, 4Oncology Department, Herbert J Thomas Memorial Hospital, South Charleston, WV, 5Baylor Scott & White Medical Center - Waxahachie, Waxahachie, TX, USA Background: Metastatic head and neck squamous cell carcinoma (HNSCC) carries a very poor prognosis. A better understanding of the molecular driver of the disease and the identification of biomarkers of response remain paramount for an effective personalized therapy. Case report: We report an original case of a 56-year-old patient diagnosed with metastatic HNSCC to both kidneys, who experienced a long-lasting complete response to a single-agent cetuximab, a monoclonal antibody-targeting EGFR. Comprehensive multiplatform biomarker analysis of the tumor revealed the presence of phosphatidyl-inositol 3 kinase mutation, EGFR overexpression, and the absence of PD-1/PD-L1 expression. Since PI3K, a downstream effector of EGFR, is activated, the tumor regression may have occurred mainly through a cetuximab-induced immune-mediated response, rather than EGFR signal blockade. It is plausible that this effect was enhanced by the lack of PD-1 and PD-L1 expression. Conclusion: Our case proposes that the absence of PD-1 and PD-L1 expression in conjunction with EGFR overexpression may correlate with better response to cetuximab in HNSCC. This hypothesis needs to be examined through a large clinical trial. Keywords: biomarker, cetuximab, EGFR blockade, exceptional response, head and neck squamous cell carcinom

Anomalous behaviour of very low frequency signals during the earthquake events

333-339The seismo-ionospheric coupling has been extensively studied in the recent years adopting various ionospheric parameters, like the critical frequency of F2 and Es layers and total electron content (TEC). There have been reports of seismic signatures in the amplitude and phase of the very low frequency (VLF) waves when an intense earthquake occurs near the propagation path. In the present paper, the amplitude of VLF waves transmitted from GQD (UK), GBZ (UK) and TBB (Turkey) received in South France during the period 2010-2013 has been studied for the precursory effect of earthquakes on the morning and evening terminator timings (TT). Six earthquake events of magnitude greater than 5 have been considered. The results of the present study show that the evening terminator undergoes many fluctuations during the pre-earthquake period of 5-15 days. But the pre-earthquake fluctuations in the morning terminator are predominant for three events, namely 8 March 2010, 11 April 2010 and 22 May 2012. The VLF day (time between morning terminator and evening terminator) is observed to be longer in the pre-earthquake period for three events