Targeting NKG2D ligands in glioblastoma with a bispecific T-cell engager is augmented with conventional therapy and enhances oncolytic virotherapy of glioma stem-like cells.

Background: Glioblastoma (GBM) almost invariably becomes resistant towards conventional treatment of radiotherapy and temozolomide (TMZ) chemotherapy, partly due to subpopulations of intrinsically resistant glioma stem-like cells (GSC). The oncolytic herpes simplex virus-1 G207 is a promising approach for GBM virotherapy although its efficacy in patients with GBM is often limited. Natural killer group 2 member D ligands (NKG2DLs) are minimally expressed by healthy cells but are upregulated by the DNA damage response (DDR) and in malignant cells with chronic DDR signaling, resulting in innate immune activation.

A framework for the systematic evaluation of a novel cigarette filter technology.

Any functional change in cigarette filter design warrants a rigorous assessment to ensure comparability to existing filter functionality. This study compares the functionality of a standard CA filter with a novel cellulose-based alternative using a combination of emissions, in silico approaches, pre-clinical assessments and behavioural studies. We assess the challenges faced with a significant filtration change, the substantiation of this change and the limitations of such assessments.

Oncolytic viruses and antibodies: are they more successful when delivered separately or when engineered as a single agent?

Oncolytic viruses (OVs) provide the promise of tumor-selective cytotoxicity coupled with amplification of the therapeutic agent (the virus) within the tumor improving its therapeutic index. Despite this promise, however, single agent-treatments have not been as successful as combination therapies, particularly combining with checkpoint inhibitor antibodies. The antibodies may be delivered by two approaches, either encoded within the OV genome to restrict antibody production to sites of active virus infection or alternatively given alongside OVs as separate treatments.

Inhibiting the Musculoskeletal Pathological Processes in Post-knee Replacement Surgery With Osteopathic Manipulative Treatment: A Systematic Review.

Total knee arthroplasty (TKA) is a very common surgical treatment approach for severe osteoarthritis. Complications of TKA include loss of range of motion and prolonged analgesic requirement for pain control. Osteopathic manipulative techniques (OMT) have been utilized to address localized muscular stiffness to improve range of motion; however, limited studies directly correlate OMT and TKA recovery.

Palliative Medicine in Myelodysplastic Syndromes: Patients and Caregivers - A Qualitative Study.

Objectives: Evidence-based guidelines call for integration of palliative care within oncology from diagnosis. Misperceptions about palliative care have impeded implementation. Prior research has not examined perceptions about 'palliative care' versus 'supportive care' among patients and caregivers to whom this care is introduced routinely as part of comprehensive cancer care.

Beyond cancer cells: Targeting the tumor microenvironment with gene therapy and armed oncolytic virus.

Cancer gene therapies are usually designed either to express wild-type copies of tumor suppressor genes or to exploit tumor-associated phenotypic changes to endow selective cytotoxicity. However, these approaches become less relevant to cancers that contain many independent mutations, and the situation is made more complex by our increased understanding of clonal evolution of tumors, meaning that different metastases and even regions of the same tumor mass have distinct mutational and phenotypic profiles. In contrast, the relatively genetically stable tumor microenvironment (TME) therefore provides an appealing therapeutic target, particularly since it plays an essential role in promoting cancer growth, immune tolerance, and acquired resistance to many therapies.

Role of Nurr1 in Carcinogenesis and Tumor Immunology: A State of the Art Review.

Nuclear receptor related-1 protein (Nurr1), coded by an early response gene, is involved in multiple cellular and physiological functions, including proliferation, survival, and self-renewal. Dysregulation of Nurr1 has been frequently observed in many cancers and is attributed to multiple transcriptional and post-transcriptional mechanisms. Besides, Nurr1 exhibits extensive crosstalk with many oncogenic and tumor suppressor molecules, which contribute to its potential pro-malignant behaviors.

HPV-induced Nurr1 promotes cancer aggressiveness, self-renewal, and radioresistance via ERK and AKT signaling in cervical cancer.

Human papillomavirus (HPV) is the etiological agent of cervical cancer; however, the mechanisms underlying HPV-mediated carcinogenesis remain poorly understood. Here, we showed that nuclear receptor related-1 protein (Nurr1) was upregulated in primary cervical cancer tissue-derived spheroid cells and HPV-positive cell lines, and Nurr1 upregulation was correlated with cancer grade. Nurr1 promoted cell proliferation, migration, invasion, and anchorage-independent cell growth.

CD109 mediates tumorigenicity and cancer aggressiveness via regulation of EGFR and STAT3 signalling in cervical squamous cell carcinoma.

Background: CD109 was involved in the tumorigenesis and progression of various cancers via TGF-β1 signalling and STAT3 activation. As CD109 is strongly expressed in cervical squamous cell carcinoma, this study was conducted to investigate its functional characteristics in cervical cancer.

Methods: CD109 expression was examined by immunohistochemistry (IHC) with cervical tissue microarray.

Perceptions of the osteopathic profession in New York City's Chinese Communities.

Objective: The purpose of this study was to assess knowledge of and barriers to osteopathic medicine in Chinese immigrant communities in New York City (NYC).

Design: A cross-sectional study was designed in which a culturally appropriate survey in Chinese and English versions was administered anonymously to measure immigrant perceptions and knowledge of osteopathic medicine.

Setting: Data collection occurred in the municipal delineations for the Chinatown neighbourhood within the New York, New York borough of Manhattan.

Giving Voice to Patient Values Throughout Cancer: A Novel Nurse-Led Intervention.

Context: Optimal advance care planning allows patients to articulate their values as a touchstone for medical decision making. Ideally, this occurs when patients are clinically stable, and with opportunities for iteration as the clinical situation unfolds.

Objectives: Testing feasibility and acceptability in busy outpatient oncology clinics of a novel program of systematic, oncology nurse-led values discussions with all new cancer patients.

A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies.

Purpose: Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways. Preclinical data indicates that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs.

Methods: This is a single-center, open-label, phase 1 trial of ADI-PEG 20 and modified FOLFOX6 (mFOLFOX6) in treatment-refractory hepatocellular carcinoma (HCC) and other advanced gastrointestinal tumors.

Photochemical Formation of Anthracene Quinone Methide Derivatives.

Anthrols 2-7 were synthesized and their photochemical reactivity investigated by irradiations in aq CHOH. Upon excitation with visible light (λ > 400 nm) in methanolic solutions, they undergo photodehydration or photodeamination and deliver methyl ethers, most probably via quinone methides (QMs), with methanolysis quantum efficiencies Φ = 0.02-0.

Phase Ib study of codrituzumab in combination with sorafenib in patients with non-curable advanced hepatocellular carcinoma (HCC).

Purpose: Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC.

Patients And Methods: In a 3 + 3 design, codrituzumab was given intravenously in various doses with sorafenib 400 mg twice daily to patients with advanced HCC, age ≥18, ECOG 0-1, Child-Pugh A and B7, adequate organ functions, and no prior systemic therapy, with tumor assessment by RECIST 1.

Reactivity of Cations and Zwitterions Formed in Photochemical and Acid-Catalyzed Reactions from m-Hydroxycycloalkyl-Substituted Phenol Derivatives.

Three m-substituted phenol derivatives, each with a labile benzylic alcohol group and bearing either protoadamantyl 4, homoadamantyl 5, or a cyclohexyl group 6, were synthesized and their thermal acid-catalyzed and photochemical solvolytic reactivity studied, using preparative irradiations, fluorescence measurements, nanosecond laser flash photolysis, and quantum chemical calculations. The choice of m-hydroxy-substitution was driven by the potential for these phenolic systems to generate m-quinone methides on photolysis, which could ultimately drive the excited-state pathway, as opposed to forming simple benzylic carbocations in the corresponding thermal route. Indeed, thermal acid-catalyzed reactions gave the corresponding cations, which undergo rearrangement and elimination from 4, only elimination from 5, and substitution and elimination from 6.

Photocyclization and Photoaddition Reactions of Arylphenols via Intermediate Quinone Methides.

A series of five benzannelated derivatives of 2-phenylphenol were prepared, and their photochemistry was investigated. Two of these (3-phenyl-2-naphthol, 10, and 1-phenyl-2-naphthol, 11) were photoinert. For 2-(1-naphthyl)phenol (12) and 1-(1-naphthyl)-2-naphthol (13), ESPT took place to either the 2'-position or the 7'-position of the naphthalene ring to give quinone methides (QMs) that underwent either reverse proton transfer (RPT) or electrocyclic ring closure to give dihydrobenzoxanthenes.

Ketoprofen as a photoinitiator for anionic polymerization.

A new photoinitiating system for anionic polymerization of acrylates based on the efficient photodecarboxylation of Ketoprofen (1) and the related derivatives 3 and 4 that generate the corresponding carbanion intermediates is presented. Carbanion intermediates are confirmed by deuterium incorporation in the trapped Michael adducts and by spectroscopic detection using laser flash photolysis (LFP). This novel anionic initiating system features excitation in the near UV and visible regions, potential characteristics of photocontrolled living polymerization, and metal-free photoinitiators generated from photoexcitation, different from typical anionic polymerization where the polymerizations are initiated by heat and strong base containing alkali metals.

Enhancement of antiproliferative activity by phototautomerization of anthrylphenols.

An antiproliferative investigation was conducted on 3 human cancer cell lines, HCT 116 (colon), MCF-7 (breast), and H 460 (lung), on a series of 4 anthrylphenols in the dark and upon exposure to light (350 nm). 9-(2-Hydroxyphenyl)anthracene (1) moderately inhibited proliferation, but irradiation considerably enhanced the effect. The other anthracenes 4–6 exhibited antiproliferative activity in the dark, which was not enhanced upon irradiation.

Observation of excited state proton transfer reactions in 2-phenylphenol and 2-phenyl-1-naphthol and formation of quinone methide species.

The excited state intramolecular proton transfer (ESIPT) reactions from a phenol (naphthol) to a carbon atom in the adjacent aromatic ring of 2-phenylphenol (1) and 2-phenyl-1-naphthol (4) are prototypical examples of intramolecular proton transfer not mediated by solvent molecules. Femtosecond time-resolved transient absorption (fs-TA) studies are conducted for the first time to directly probe the formation of quinone methide (QM) species generated from the ESIPT pathways of 1 and 4. Steady-state absorption experiments demonstrated 1 exists mainly in its non-deprotonated form in neat MeCN and in water-MeCN solutions.

Near-visible light generation of a quinone methide from 3-hydroxymethyl-2-anthrol.

Excitation of 2-hydroxy-3-(diphenylhydroxymethyl)anthracene (7) to S1 initiates photodehydration, giving the corresponding quinone methide (QM) that was detected by laser flash photolysis (LFP) in 2,2,2-trifluoroethanol (λ = 580 nm, τ = 690 ± 10 ns). The QM decays by protonation, giving a cation (λ = 520 nm, τ = 84 ± 3 μs), which subsequently reacts with nucleophiles. The rate constants in the reactions with nucleophiles were determined by LFP, whereas the adducts were isolated via preparative photolyses.

Photosolvolysis of bulky (4-hydroxyphenyl)naphthalene derivatives.

Six new naphthylphenols , bearing bulky hydroxymethyl substituents on the naphthalene, were synthesized and their photoreactivity was investigated by preparative irradiation, fluorescence measurements, and laser flash photolysis. All derivatives (in S1) undergo deprotonation of the phenolic OH in the aqueous solution. Also, fluorescence quenching with HClO4 in the pH range 2-4 indicates that can be protonated in S1.

Solvent-dependent excited state intramolecular proton transfer (ESIPT) pathways from phenol to carbon in 2,5-dihydroxyphenyl arenes.

The ESIPT of three 2,5-dihydroxyphenyl-substituted arenes 9-11 was studied in various solvent systems, to investigate the direction of the proton transfer from the phenol to the respective carbons of naphthyl, phenanthrenyl and anthryl aromatic rings. In neat CH3CN, 9-11 undergo direct ESIPT from the phenolic OH to the ipso-position of the corresponding aromatic carbon acceptors, via an intramolecular charge transfer state (S(1,ct)), giving rise to observable zwitterions, ZIs 35, 25, 27, respectively. Surprisingly, the generated ZI in 9 proceeds via a 1,2-phenyl migration followed by re-aromatization to afford 16 (a structural isomer of 9) in quantitative yield.

Excited state intramolecular proton transfer (ESIPT) from phenol to carbon in selected phenylnaphthols and naphthylphenols.

ESIPT and solvent-assisted ESPT in isomeric phenyl naphthols and naphthyl phenols 5-8 were investigated by preparative photolyses in CH3CN-D2O, fluorescence spectroscopy, LFP, and ab initio calculations. ESIPT takes place only in 5 (D-exchange Φ = 0.3), whereas 6-8 undergo solvent-assisted PT with much lower efficiencies.

Very efficient generation of quinone methides through excited state intramolecular proton transfer to a carbon atom.

Irradiation of 2-phenyl-1-naphthol (6) in CH(3) CN/D(2) O (3:1) leads to very efficient incorporation of deuterium at the ortho-positions of the adjacent phenyl ring (overall Φ=0.73±0.07), along with minor incorporation at the naphthalene positions 5 and 8.

Sterically congested adamantylnaphthalene quinone methides.

Five new (2-adamantyl)naphthol derivatives (5-9, quinone methide precursors, QMP) were synthesized and their photochemical reactivity was investigated by preparative photolyses, fluorescence spectroscopy, and laser flash photolysis (LFP). Excitation of QMP 5 to S(1) leads to efficient excited state intramolecular proton transfer (ESIPT) coupled with dehydration, giving quinone methide QM5 which was characterized by LFP (in CH(3)CN-H(2)O, λ(max) = 370 nm, τ = 0.19 ms).