Nickel Pincer Complexes Catalyzed Sustainable Synthesis of 3,4-Dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxides via Acceptorless Dehydrogenative Coupling of Primary Alcohols.

We report the atom-economic and sustainable synthesis of biologically important 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide (DHBD) derivatives from readily available aromatic primary alcohols and 2-aminobenzenesulfonamide catalyzed by nickel(II)-N∧N∧S pincer-type complexes. The synthesized nickel complexes have been well-studied by elemental and spectroscopic (FT-IR, NMR, and HRMS) analyses. The solid-state molecular structure of complex 2 has been authenticated by a single-crystal X-ray diffraction study. Furthermore, a series of 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide derivatives have been synthesized (24 examples) utilizing a 3 mol % Ni(II) catalyst through acceptorless dehydrogenative coupling of benzyl alcohols with benzenesulfonamide. Gratifyingly, the catalytic protocol is highly selective with the yield up to 93% and produces eco-friendly water/hydrogen gas as byproducts. The control experiments and plausible mechanistic investigations indicate that the coupling of the in situ generated aldehyde with benzenesulfonamide leads to the desired product. In addition, a large-scale synthesis of one of the thiadiazine derivatives unveils the synthetic usefulness of the current methodology.

NNO Pincer-Supported Pd(II)-Catalyzed Reductive N-Alkylation of Challenging Nitroarenes with Alcohols via Borrowing Hydrogen Strategy.

A sustainable catalytic synthesis of selective monoalkylated amines from nitroarenes and alcohols by new palladium(II)-NNO pincer-type complexes has been described. Herein, a series of Pd(II) complexes [Pd(NNO)PPh3] (1-3) are synthesized and characterized by analytical and spectroscopic (IR, NMR, and HR-MS) methods. The solid-state molecular structures of two complexes are established by X-ray single-crystal diffraction. Furthermore, the catalytic N-alkylation of challenging nitroarenes with primary and secondary alcohols has been performed by the well-defined palladium(II) complexes via borrowing hydrogen strategy. The current protocol offers a wide range of monoalkylated amines (26 examples) with a maximum yield of 87% utilizing 1 mol % of catalyst loading. Gratifyingly, the catalytic system works well under mild reaction conditions and atom economy with water is the only byproduct. Furthermore, control experiments confirm the formation of probable intermediates (aniline, aldehyde, and imine), and deuterium labeling authenticates the borrowing hydrogen mechanism. A gram-scale synthesis of an alkylated product clearly demonstrates the synthetic efficacy of the present catalytic methodology.

One-Pot Sustainable Synthesis of Highly Substituted Pyrimidines via Acceptorless Dehydrogenative Annulation of Alcohols Using Pincer Ni(II)-NNS Catalysts.

We report an efficient and sustainable synthesis of highly substituted pyrimidines promoted by nickel(II)-NNS pincer-type complexes via acceptorless dehydrogenative annulations of readily available alcohols, malononitrile, and guanidine/benzamidine salt under eco-friendly conditions for the first time. Different sets of Ni(II) complexes (C1-C3) encapsulated in NNS pincer-type thiosemicarbazone ligands have been synthesized and authenticated by analytical and spectroscopic (Fourier transform infrared, nuclear magnetic resonance, and high-resolution mass spectrometry) techniques. The solid state three-dimensional structure of a representative complex (C2) has been determined with the aid of single crystal XRD analysis and confirms a square planar architecture around the nickel ion. Further, the well-defined Ni(II) complexes have been employed as efficient catalysts for the fabrication of a wide range of 4-aminopyrimidine-5-carbonitrile derivatives (33 examples) from readily available alcohols with suitable coupling partners such as malononitrile and guanidine/benzamidine under eco-friendly conditions. The current catalytic approach affords maximum yields up to 95% utilizing 3 mol % catalyst loading and water/hydrogen as the only byproduct. A feasible catalytic pathway has been proposed based on the different control experiment reactions, which clearly indicate that the coupling reaction proceeds via aldehyde and benzylidenemalononitrile intermediates. The practicability of the current protocol has been demonstrated by the large-scale synthesis of one of the products, 4-amino-2,6-diphenylpyrimidine-5-carbonitrile, and a short synthesis of a cytosine antifungal analogue.

Promoting the Anticancer Activity with Multidentate Furan-2-Carboxamide Functionalized Aroyl Thiourea Chelation in Binuclear Half-Sandwich Ruthenium(II) Complexes.

A new set of binuclear arene ruthenium complexes [Ru2(p-cymene)2(k4-N2OS)(L1-L3)Cl2] (Ru2L1-Ru2L3) encompassing furan-2-carboxamide-based aroylthiourea derivatives (H2L1-H2L3) was synthesized and characterized by various spectral and analytical techniques. Single-crystal XRD analysis unveils the N^O and N^S mixed monobasic bidentate coordination of the ligands constructing N, S, Cl/N, O, and Cl legged piano stool octahedral geometry. DFT analysis demonstrates the predilection for the formation of stable arene ruthenium complexes. In vitro antiproliferative activity of the complexes was examined against human cervical (HeLa), breast (MCF-7), and lung (A549) cancerous and noncancerous monkey kidney epithelial (Vero) cells. All the complexes are more efficacious against HeLa and MCF-7 cells with low inhibitory doses (3.86-11.02 µM). Specifically, Ru2L3 incorporating p-cymene and -OCH3 fragments exhibits high lipophilicity, significant cytotoxicity against cancer cells, and lower toxicity on noncancerous cells. Staining analysis indicates the apoptosis-associated cell morphological changes expressively in MCF-7 cells. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) analyses reveal that Ru2L3 can raise ROS levels, reduce MMP, and trigger mitochondrial dysfunction-mediated apoptosis. The catalytic oxidation of glutathione (GSH) to its disulfide form (GSSG) by the complexes may simultaneously increase the ROS levels, alluding to their observed cytotoxicity and apoptosis induction. Flow cytometry determined the quantitative classification of late apoptosis and S-phase arrest in MCF-7 and HeLa cells. Western blotting analysis confirmed that the complexes promote apoptosis by upregulating Caspase-3 and Caspase-9 and downregulating BCL-2. Molecular docking studies unfolded the strong binding affinities of the complexes with VEGFR2, an angiogenic signaling receptor, and BCL2, Cyclin D1, and HER2 proteins typically overexpressed on tumor cells.

Focal therapy for oligometastatic and oligoprogressive renal cell carcinoma: a narrative review.

Metastatic renal cell carcinoma (RCC) can present with oligometastatic disease and/or develop oligoprogression following systemic therapy. Cytoreductive and focal metastasis-directed therapy options include resection, stereotactic ablative radiation and thermal ablation. Aggressive focal therapy may allow delay in initiation of or modification to systemic therapy and improve clinical outcomes. In this narrative review we synthesize current practice guidelines and prospective data on focal therapy management options and highlight future research. Patient selection and the choice of focal treatment techniques are controversial due to limited and heterogeneous data and patients may benefit from multidisciplinary evaluation. Prospective comparative trials with clearly defined inclusion criteria and relevant end points are needed to clarify the risks and benefits of different approaches.

[Box: see text].

Arene Ruthenium(II)-Catalyzed Sustainable Synthesis of 2,4-Disubstituted Quinazolines via Acceptorless Dual Dehydrogenative Coupling of Alcohols.

We demonstrate an efficient and sustainable strategy for the direct synthesis of 2,4-disubstituted quinazolines by arene Ru(II)benzhydrazone complex via the eco-friendly sequential acceptorless dehydrogenative coupling of 2-aminobenzhydrol derivatives and benzyl alcohols for the first time. The new ruthenium(II) complex of the general formula [(η6-p-cymene)Ru(L1)Cl] (L1-acenaphthenequinone hydrazone) has been synthesized and characterized by analytical, spectroscopic, and single-crystal X-ray diffraction techniques. A broad spectrum of 2,4-disubstituted quinazolines have been successfully derived (25 examples) from 2-aminobenzhydrol derivatives with various benzyl alcohols using 1 mol % of catalyst loading in the presence of NH4OAc. The present protocol is highly selective and produces a maximum yield of 95% under mild reaction conditions. The different reaction intermediates detected through control experiments such as aldehyde, 2-aminobenzophenone, benzylidene(amino)phenylmethanone, and 1,2-dihydroquinazoline are isolated and authenticated by the NMR study. Gratifyingly, the coupling reaction is a simple and atom economic with the release of water and hydrogen gas as the only byproducts. A gram-scale synthesis of 2-(4-methoxyphenyl)-4-phenylquinazoline illustrates the synthetic utility of the present protocol.

The Impact of COVID-19 on US Radiation Oncology Residents.

The purpose of our study is to assess the impact of COVID-19 on the clinical responsibilities, training, and wellness of US radiation oncology residents. An anonymous cross-sectional survey was sent to all 91 radiation oncology residency programs in the USA. The survey included questions related to demographics, changes in clinical duties and training, job prospects, and wellness indicators. Univariate and multivariate logistic regression analyses were used to evaluate factors associated with residents endorsing high satisfaction with their departments' response to COVID-19. A total of 96 residents completed the survey from 67 US radiation oncology programs. In the multivariate logistic regression model, remote contouring (OR: 3.91 (95% CI: 1.11, 13.80), p = 0.03) and belief that one will be adequately trained to independently practice after completing residency (OR: 4.68 (1.12, 19.47), p = 0.03) were significantly associated with high resident satisfaction with their department's response to COVID-19. Most residents indicated that hypofractionation was encouraged to a greater extent (n = 79, 82.3%), patients were triaged by disease risk (n = 67, 69.8%), and most agreed/strongly agreed that they have been provided with adequate personal protective equipment (PPE) (n = 85, 88.5%). The COVID-19 pandemic has affected the training and wellness of radiation oncology residents. Our analysis suggests that radiation oncology programs might increase resident satisfaction with their department's response to COVID-19 by enabling remote contouring and working with residents to identity and remedy possible concerns regarding their ability to independently practice post residency.

Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.

Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.

NCCN Guidelines Insights: Uveal Melanoma, Version 1.2019.

The NCCN Guidelines for Uveal Melanoma include recommendations for staging, treatment, and follow-up of patients diagnosed with uveal melanoma of the choroid or ciliary body. In addition, because distinguishing between uveal melanoma and benign uveal nevi is in some cases difficult, these guidelines also contain recommendations for workup of patients with suspicious pigmented uveal lesions, to clarify the tests needed to distinguish between those who should have further workup and treatment for uveal melanoma versus those with uncertain diagnosis and low risk who should to be followed and later reevaluated. These NCCN Guidelines Insights describe recommendations for treatment of newly diagnosed nonmetastatic uveal melanoma in patients who have already undergone a complete workup.

Direct synthesis of 2,4,5-trisubstituted imidazoles from primary alcohols by diruthenium(ii) catalysts under aerobic conditions.

Herein we report a straightforward synthetic approach to 2,4,5-trisubstituted imidazoles from readily available primary alcohols using arene diruthenium(ii) catalysts. Dinuclear arene ruthenium complexes have been synthesized and structurally characterized with the aid of analytical and spectral techniques. A library of 2,4,5-trisubstituted imidazoles was achieved with a yield up to 95% by loading 0.25 mol% of the catalyst. The present protocol is environmentally benign, which is performed under aerobic conditions and liberates water as the sole by-product.

Prospective study of proton-beam radiation therapy for limited-stage small cell lung cancer.

BACKGROUND: Existing data supporting the use of proton-beam therapy (PBT) for limited-stage small cell lung cancer (LS-SCLC) are limited to a single 6-patient case series. This is the first prospective study to evaluate clinical outcomes and toxicities of PBT for LS-SCLC. METHODS: This study prospectively analyzed patients with primary, nonrecurrent LS-SCLC definitively treated with PBT and concurrent chemotherapy from 2011 to 2016. Clinical backup intensity-modulated radiotherapy (IMRT) plans were generated for each patient and were compared with PBT plans. Outcome measures included local control (LC), recurrence-free survival (RFS), and overall survival (OS) rates and toxicities. RESULTS: Thirty consecutive patients were enrolled and evaluated. The median dose was 63.9 cobalt gray equivalents (range, 45-66.6 cobalt gray equivalents) in 33 to 37 fractions delivered daily (n = 18 [60.0%]) or twice daily (n = 12 [40.0%]). The concurrent chemotherapy was cisplatin/etoposide (n = 21 [70.0%]) or carboplatin/etoposide (n = 9 [30.0%]). In comparison with the backup IMRT plans, PBT allowed statistically significant reductions in the cord, heart, and lung mean doses and the volume receiving at least 5 Gy but not in the esophagus mean dose or the lung volume receiving at least 20 Gy. At a median follow-up of 14 months, the 1-/2-year LC and RFS rates were 85%/69% and 63%/42%, respectively. The median OS was 28.2 months, and the 1-/2-year OS rates were 72%/58%. There was 1 case each (3.3%) of grade 3 or higher esophagitis, pneumonitis, anorexia, and pericardial effusion. Grade 2 pneumonitis and esophagitis were seen in 10.0% and 43.3% of patients, respectively. CONCLUSIONS: In the first prospective registry study and largest analysis to date of PBT for LS-SCLC, PBT was found to be safe with a limited incidence of high-grade toxicities. Cancer 2017;123:4244-4251. © 2017 American Cancer Society.

Framework for radiation pneumonitis risk stratification based on anatomic and perfused lung dosimetry.

PURPOSE: To design and apply a framework for predicting symptomatic radiation pneumonitis in patients undergoing thoracic radiation, using both pretreatment anatomic and perfused lung dose-volume parameters. MATERIALS AND METHODS: Radiation treatment planning CT scans were coregistered with pretreatment [99mTc]MAA perfusion SPECT/CT scans of 20 patients who underwent definitive thoracic radiation. Clinical radiation pneumonitis was defined as grade ≥ 2 (CTCAE v4 grading system). Anatomic lung dose-volume parameters were collected from the treatment planning scans. Perfusion dose-volume parameters were calculated from pretreatment SPECT/CT scans. Equivalent doses in 2 Gy per fraction were calculated in the lung to account for differences in treatment regimens and spatial variations in lung dose (EQD2lung). RESULTS: Anatomic lung dosimetric parameters (MLD) and functional lung dosimetric parameters (pMLD70%) were identified as candidate predictors of grade ≥ 2 radiation pneumonitis (AUC > 0.93, p < 0.01). Pairing of an anatomic and functional dosimetric parameter (e. g., MLD and pMLD70%) may further improve prediction accuracy. Not all individuals with high anatomic lung dose (MLD > 13.6 GyEQD2lung, 19.3 Gy for patients receiving 60 Gy in 30 fractions) developed radiation pneumonitis, but all individuals who also had high mean dose to perfused lung (pMLD70% > 13.3 GyEQD2) developed radiation pneumonitis. CONCLUSIONS: The preliminary application of this framework revealed differences between anatomic and perfused lung dosimetry in this limited patient cohort. The addition of perfused lung parameters may help risk stratify patients for radiation pneumonitis, especially in treatment plans with high anatomic mean lung dose. Further investigations are warranted.

Combination of stereotactic ablative body radiation with targeted therapies.

Recent advances allow safe and effective delivery of ablative doses of radiation with stereotactic precision to tumours, resulting in very high levels of tumour control. Parallel advances in the understanding of tumour biology enable delivery of systemic drugs that selectively antagonise biological pathways in the tumour and surrounding microenvironment. Data is emerging that these treatments have synergistic effects that might further increase therapeutic efficacy, and they are therefore being increasingly used in combination, primarily in metastatic or recurrent disease. In this Review we summarise the biological rationale and clinical data for both sterotactic ablative radiotherapy (SABR) and targeted therapies, and the emerging experience with combination of these treatments. We describe potential pathways of cooperation in both tumour and normal tissue between SABR and targeted drugs, and, because fatal toxicities have been reported, we outline clinical precautions.

Analysis of antiproliferative activity of new half-sandwich arene Ru(II) thiophene based aroylhydrazone complexes.

Efforts in researching the efficient anti-tumor properties of three novel arene ruthenium(II) complexes incorporating thiophene-based aroylhydrazone ligands have been undertaken. The complexes' elemental composition was [(η6-p-cymene)Ru(L)Cl]. They were comprehensively characterized through elemental and spectroscopic analyses (FT-IR, UV-vis, NMR, and HR-MS). Single crystal X-ray diffraction studies revealed a pseudo-octahedral geometry with bidentate coordination of the ligands in a representative complex. The in vitro assessment of the complexes' cancer cell growth inhibition was conducted using the MTT assay against A549 (human lung carcinoma), HeLa (human cervical carcinoma), HuH-7 (hepatocellular carcinoma), and NIH-3T3 (mouse fibroblast non-cancerous cell line). Results indicated significant cytotoxicity across all cancer cell lines, with IC50 concentrations of complex 2 being 6.8 µM for A549, 11.6 µM for HeLa, and 9.4 µM for HuH-7, compared to cisplatin with IC50 values of 18.9 µM, 17.68 µM, and 24 µM respectively. Notably, complex 2 demonstrated particularly promising cytotoxicity against all tested cancerous cell lines. Fluorescent staining analysis such as acridine orange/ethidium bromide (AO-EB) and HOECHST 33342 revealed cell death mechanisms involving membrane disintegration and nuclear condensation following treatment with complex 2. Further studies were conducted to measure reactive oxygen species (ROS) levels using the dichlorodihydrofluorescein diacetate (DCFH-DA) assay, and mitochondrial membrane potential (MMP) was assessed using the JC-1 dye assay. These studies demonstrated that complex 2 increased ROS levels, decreased membrane potential, and promoted mitochondrial dysfunction-mediated cell death pathways. Additionally, flow cytometry analysis, utilizing dual staining of Annexin V-FITC and propidium iodide (PI), was employed to quantitatively study apoptosis induction.

Preclinical Ultra-High Dose Rate (FLASH) Proton Radiation Therapy System for Small Animal Studies.

Purpose: Animal studies with ultrahigh dose-rate radiation therapy (FLASH, >40 Gy/s) preferentially spare normal tissues without sacrificing antitumor efficacy compared with conventional dose-rate radiation therapy (CONV). At the University of Washington, we developed a cyclotron-generated preclinical scattered proton beam with FLASH dose rates. We present the technical details of our FLASH radiation system and preliminary biologic results from whole pelvis radiation. Methods and Materials: A Scanditronix MC50 compact cyclotron beamline has been modified to produce a 48.7 MeV proton beam at dose rates between 0.1 and 150 Gy/s. The system produces a 6 cm diameter scattered proton beam (flat to ± 3%) at the target location. Female C57BL/6 mice 5 to 6 weeks old were used for all experiments. To study normal tissue effects in the distal colon, mice were irradiated using the entrance region of the proton beam to the whole pelvis, 18.5 Gy at different dose rates: control, CONV (0.6-1 Gy/s) and FLASH (50-80 Gy/s). Survival was monitored daily and EdU (5-ethynyl-2´-deoxyuridine) staining was performed at 24- and 96-hours postradiation. Cleaved caspase-3 staining was performed 24-hours postradiation. To study tumor control, allograft B16F10 tumors were implanted in the right flank and received 18 Gy CONV or FLASH proton radiation. Tumor growth and survival were monitored. Results: After 18.5 Gy whole pelvis radiation, survival was 100% in the control group, 0% in the CONV group, and 44% in the FLASH group (P < .01). EdU staining showed cell proliferation was significantly higher in the FLASH versus CONV group at both 24-hours and 96-hours postradiation in the distal colon, although both radiation groups showed decreased proliferation compared with controls (P < .05). Lower cleaved caspase-3 staining was seen in the FLASH versus conventional group postradiation (P < .05). Comparable flank tumor control was observed in the CONV and FLASH groups. Conclusions: We present our preclinical FLASH proton radiation system and biologic results showing improved survival after whole pelvis radiation, with equivalent tumor control.

High body mass index is associated with worse quality of life in breast cancer patients receiving radiotherapy.

The purpose of this study was to examine the impact of body mass index (BMI) on breast cancer patients' self-reported health-related quality of life among patients treated with radiation therapy (RT). Women with breast cancer undergoing RT were prospectively enrolled in an Institutional Review Board-approved clinical trial between 2009 and 2012. Quality of life (QOL) assessments were collected pre-RT, during RT, and within 3 months post-RT using Euroqol (EQ-5D), MD Anderson Symptom Inventory, and functional assessment of cancer therapy-general (FACT-G). 183 breast cancer patients were enrolled, of whom 140 completed assessments at one or more time-point. After adjusting for age, chemotherapy, prior RT, type of breast surgery, and comorbidities, higher BMI remained significantly associated with worse QOL pre-RT, during RT, and post-RT in breast cancer patients. Higher BMI was strongly associated with worse overall FACT-G score on treatment and greater decline in physical well-being on treatment, which persisted after treatment. While effects on QOL of patients in the underweight and normal weight group peaked during treatment, rapidly improving by follow-up, obese patients had worse functional well-being that was more persistent at follow-up. Higher BMI was associated with worse QOL for breast cancer patients before, during, and after RT, and also was associated with reduced return to baseline QOL 3 months post-RT.

Effect of HIV on survival in patients with non-small-cell lung cancer in the era of highly active antiretroviral therapy: a population-based study.

BACKGROUND: HIV-infected patients with lung cancer have been reported to have poorer survival than uninfected patients. Whether this outcome holds true in the era of highly active antiretroviral therapy (HAART) is unclear. We examined the effect of HIV infection on clinical outcome in patients with lung cancer who are also receiving HAART. METHODS: Patients diagnosed with non-small-cell lung cancer (NSCLC) from Jan 1, 2000, to Dec 31, 2005, with or without HIV infection were identified by querying the Surveillance, Epidemiology, and End Results registry and the Medicare lung cancer database. Survival analysis by stage and treatment delivered comparing the HIV-infected patients with uninfected controls was done with Kaplan-Meier and Cox models with propensity score adjustments. FINDINGS: 71,976 patients with NSCLC were identified as uninfected controls and 322 patients with NSCLC were identified in the HIV group; median age was 75 years for both groups. Median overall survival for all stages was 7·0 months (95% CI 7·0-7·0) for uninfected controls versus 8·0 months (6·0-10·0) for the HIV group (p=0·16); for those with stage I/II disease it was 37·0 months (36·0-39·0) versus 43·0 months (26·0-58·0; p=0·37); for those with stage IIIA/IIIB disease it was 7·0 months (7·0-7·0) versus 3·0 months (2·0-8·0; p=0·051); and for those with stage IV disease it was 3·0 months for both groups (95% CI 3·0-3·0 for controls; 2·0-5·0 for HIV group; p=0·77). After propensity score adjustment, the survival difference in stage IIIA/IIIB was no longer seen (hazard ratio 0·88; 95% CI 0·71-1·09). The median survival for HIV infected patients with stage I or II NSCLC who underwent surgical resection was 58·0 months (95% CI 57·0-60·0) for uninfected controls versus 50·0 months (42·0 to unestimable) for the HIV group (p=0·88). INTERPRETATION: We noted no significant difference in clinical outcome between patients with HIV and uninfected controls with NSCLC. Survival after curative surgical resection in early-stage patients was similar in HIV-infected individuals and uninfected controls. These data suggest that HIV status should not affect therapeutic decision making in NSCLC. FUNDING: US National Cancer Institute (award number UC2CA148310).

Arene Binuclear Ru(II)-Promoted Sustainable Synthesis of Substituted Pyrazoles from Alcohols via Acceptorless Dehydrogenative Annulation.

We report a selective and sustainable synthesis of substituted pyrazoles via an eco-friendly acceptorless dehydrogenative annulation (ADA) of greener alcohols, malononitrile, and various aromatic hydrazides by newly synthesized binuclear Ru(II) p-cymene complexes. A discrete set of binuclear Ru(II) complexes are fabricated and structurally characterized by analytical, spectral, and single-crystal X-ray diffraction methods. Further, the catalytic effectiveness of the complexes is explored for the construction of 5-amino-4-cyano-N-aroylpyrazoles (34 examples) under mild conditions and produces H2O/H2 as the only byproduct. A sequence of polysubstituted pyrazoles has been constructed in 62-95% yield using 1 mol % catalyst loading. Probable intermediates detected in the catalytic reaction have been isolated and confirmed by nuclear magnetic resonance and electrospray ionization mass spectrometry studies. Expediently, a therapeutically significant gout medicine "allopurinol" analogue has been derived successfully from the synthesized 5-amino-4-cyano-N-aroylpyrazoles.

Exploration of Antiproliferative Activity and Apoptosis Induction of New Nickel(II) Complexes Encompassing Carbazole Ligands.

To attest the effectiveness of nickel complexes as anticancer drug candidates with minimum side effects, the present investigation describes the facile synthesis and anticancer activities of nickel(II) complexes enriched with three derivatives of carbazolone-based benzhydrazone ligands(L) having a [Ni(L)2] composition. Analytical and spectral techniques were used to characterize the synthesized Ni(II) complexes. The single-crystal X-ray diffraction performed for complex 4 confirmed the square planar geometry with a [Ni(κ2-N,O-L)2] arrangement. The MTT assay was carried out for the complexes to determine in vitro cytotoxicity against cancerous human-cervical carcinoma, human-colon carcinoma, and non-cancerous L929 (fibroblast) cells. All three complexes exhibited good toxicity against the cancer cells with a low IC50 concentration. Complex 4, containing -OCH3 fragment, exhibits high lipophilicity and revealed exceptional cytotoxicity against cancer cells. AO-EB fluorescent staining indicated apoptosis-associated cell morphological changes after exposure to complex 4. The apoptosis induction was further confirmed by a HOECHST-33342 fluorescent staining technique via chromosomal condensation and nuclear fragmentation. Further, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) mechanistic studies revealed that complex 4 can raise ROS levels and reduce MMP and promote mitochondrial dysfunction-mediated apoptotic cell death. Further, stimulation of late apoptosis by complex 4 in cervical cancer cells was quantitatively differentiated through the staining of phosphatidylserine externalization by flow cytometry. Furthermore, the ELISA analysis confirmed that complex 4 induced apoptosis through caspase activation.