Can we predict reactivity for aromatic nucleophilic substitution with [ 18 F]fluoride ion?

The correlation between the 13 C‐NMR chemical shift of the aromatic ring carbon bearing the leaving group and the yield of nucleophilic aromatic displacement with no‐carrier‐added [ 18 F]fluoride ion was evaluated. In comparison of structurally analogous compounds (fluoro, nitro and trimethylammonium substituted benzaldehydes, benzophenones and benzonitriles), the 13 C‐NMR chemical shift of the reactive aryl ring carbon correlated quite well with the [ 18 F]fluorination yield (r 2 =0.87) for most but not all ring structures. Compounds with trimethylammonium leaving groups or methyl ring substituents were found to not fit the proposed correlation. Kinetic studies indicated clearly different rates of reaction for these compounds, with much higher than expected reactivity for the ccompounds with the cationic leaving group. Competition experiments suggest that low reactivity of methyl‐substituted rings may be due to conversion of [ 18 F]fluoride to an unreactive form. Our results indicate that the correlation between [ 18 F]fluorination yields for nucleophilic aromatic substitution reactions and the 13 C NMR chemical shift of the aryl ring carbon bearing the leaving group is applicable to numerous structurally analogous compounds, but cannot be simply generalized to aromatic rings with different leaving groups or ring substituents.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90183/1/2580330702_ftp.pd

Empiric Radiotherapy for Lung Cancer Collaborative Group multi-institutional evidence-based guidelines for the use of empiric stereotactic body radiation therapy for non-small cell lung cancer without pathologic confirmation

The standard of care for managing early stage non-small cell lung cancer (NSCLC) is definitive surgical resection. Stereotactic body radiation therapy (SBRT) has become the standard treatment for patient who are medically inoperable, and it is increasingly being considered as an option in operable patients. With the growing use of screening thoracic CT scans for patients with a history of heavy smoking, as well as improved imaging capabilities, the discovery of small lung nodes has become a common dilemma. As a result, clinicians are increasingly faced with managing lung nodules in patients in whom diagnostic biopsy is not safe or feasible. Herein, we describe the scope of the problem, tools available for predicting the probability that a lung nodule is a malignancy, staging procedures, benefits of pathology-proven and empiric SBRT, considerations of safety based on location of the lesion of concern, and overall efficacy of SBRT

Incidence of patients with bone metastases at diagnosis of solid tumors in adults: a large population-based study

Background: Bones are one of the most common metastatic sites for solid malignancies. Bone metastases can significantly increase mortality and decrease the quality of life of cancer patients. In the United States, around 350,000 people die each year from bone metastases. This study aimed to analyze and update the incidence and prognosis of bone metastases with solid tumors at the time of cancer diagnosis and its incidence rate for each solid cancer.Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to find patients diagnosed with solid cancers originating from outside the bones and joints between 2010 and 2016. Data were stratified by age, sex, and race. Patients with a tumor in situ or with an unknown bone metastases stage were excluded. We then selected most of the sites where cancer often occurred, leaving 2,207,796 patients for the final incidence analysis. For the survival analysis, patients were excluded if they were diagnosed at their autopsy or on their death certificate, or had unknown follow-ups. The incidence of bone metastases and overall survival was compared between patients with different primary tumor sites.Results: We identified 2,470,634 patients, including 426,594 patients with metastatic disease and 113,317 patients with bone metastases, for incidence analysis. The incidence of bone metastases among the metastatic subset was 88.74% in prostate cancer, 53.71% in breast cancer, and 38.65% in renal cancer. In descending order of incidence, there were patients with other cancers in the genitourinary system (except for renal, bladder, prostate, and testicular cancer) (37.91%), adenocarcinoma of the lung (ADC) (36.86%), other gynecologic cancers (36.02%), small- cell lung cancer (SCLC) (34.56%), non-small cell lung cancer not otherwise specified and others [NSCLC (NOS/others)] (33.55%), and bladder (31.08%) cancers. The rate of bone metastases is 23.19% in SCLC, 22.50% in NSCLC (NOS/others), 20.28% in ADC, 8.44% in squamous cell carcinoma of the lung (SCC), and 4.11% in bronchioloalveolar carcinoma [NSCLC (BAC)]. As for the digestive system, the overall bone metastases rate was 7.99% in the esophagus, 4.47% in the gastric cancer, 4.42% in the hepatobiliary cancer, 3.80% in the pancreas, 3.26% in other digestive organs, 1.24% in the colorectum, and 1.00% in the anus. Overall, the incidence rate of bone metastases among the entire cohort in breast and prostate cancer was 3.73% and 5.69%, respectively.Conclusions: The results of this study provide population-based estimates for the incidence rates of patients with bone metastases at initial diagnosis of their solid tumor. The findings can help clinicians to early detect bone metastases by bone screening to anticipate the occurrence of symptoms and favorably improve the prognosis

Consensus Statement on Proton Therapy in Mesothelioma

Purpose: Radiation therapy for mesothelioma remains challenging, as normal tissue toxicity limits the amount of radiation that can be safely delivered to the pleural surfaces, especially radiation dose to the contralateral lung. The physical properties of proton therapy result in better sparing of normal tissues when treating the pleura, both in the postpneumonectomy setting and the lung-intact setting. Compared with photon radiation, there are dramatic reductions in dose to the contralateral lung, heart, liver, kidneys, and stomach. However, the tissue heterogeneity in the thorax, organ motion, and potential for changing anatomy during the treatment course all present challenges to optimal irradiation with protons. Methods: The clinical data underlying proton therapy in mesothelioma are reviewed here, including indications, advantages, and limitations. Results: The Particle Therapy Cooperative Group Thoracic Subcommittee task group provides specific guidelines for the use of proton therapy for mesothelioma. Conclusions: This consensus report can be used to guide clinical practice, insurance approval, and future research

Predicting Radiation Pneumonitis after Chemoradiotherapy for Lung Cancer: An International Individual Patient Data Meta-analysis

Radiation pneumonitis is a dose-limiting toxicity for patients undergoing concurrent chemoradiation therapy (CCRT) for non-small cell lung cancer (NSCLC). We performed an individual patient data meta-analysis to determine factors predictive of clinically significant pneumonitis

Signaling actin polymerization responses in hematopoietic cells.

The polymerization and depolymerization of the cellular protein actin are thought to provide the basis for the morphological changes that are necessary for cell motility. The actin polymerization response in stimulated hematopoietic cells can be divided into discrete phases: (1) The initial actin polymerization event and (2) The gradual depolymerization of F-actin back to basal levels. An additional intermediate phase has been characterized in neutrophils stimulated with leukotriene B\sb4 or platelet activating factor. This stimulation results in the production of a rapidly oscillating actin polymerization/depolymerization response immediately subsequent to the initial actin polymerization event. Protein kinase C was implicated in mediating these F-actin oscillations by the observation that inhibition of this enzyme resulted in a masking of this response. The motor actin binding protein myosin was subsequently implicated as a downstream mediator of the F-actin oscillations by the observation that disruption of intracellular actin-myosin resulted in a masking of this response. Additionally, stimulation of neutrophils with leukotriene B\sb4 resulted in the myosin light chain being serine phosphorylated in a protein kinase C-dependent manner. This phosphorylation was shown to occur in a manner that was kinetically distinct from the myosin phosphorylation induced by n-formyl-methionyl-leucyl-phenylalanine, a potent activator of actin polymerization that alone did not induce F-actin oscillations. These data suggest that protein kinase C and downstream phosphorylation of myosin by a protein kinase C-dependent pathway may play a role in mediating the production of neutrophil F-actin oscillations. Wiskott-Aldrich Syndrome Protein (WASP), the protein identified as being defective in the disease Wiskott-Aldrich Syndrome (WAS), has been hypothesized to play a role in signaling the initial actin polymerization event. In contrast, we found that stimulated actin polymerization is kinetically normal in the hematopoietic lineages affected in WAS. We also found that the actin cytoskeleton in WAS platelets is capable of producing the hallmark cytoarchitectural features associated with activation. Further analysis revealed increased caspase-3 activity in WAS lymphocytes. This increased activity resulted in accelerated apoptosis of these cells. These data indicate that WASP does not play a universal role in signaling actin polymerization, but plays a role in delaying cell death.Ph.D.BiochemistryBiological SciencesCellular biologyHealth and Environmental SciencesImmunologyPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/131519/2/9909975.pd

Synthesis of the First Resorcin[4]arene-Functionalized Triazolium Salts and Their Use in Suzuki–Miyaura Cross-Coupling Reactions

Two bulky triazolium salts, namely 1-{4(24),6(10),12(16),18(22)-tetramethylenedioxy- 2,8,14,20-tetrapentylresorcin[4]arene-5-yl}-4-phenyl-3-methyl-1H-1,2,3-triazolium tetrafluoro borate (1) and 1,4-bis{4(24),6(10),12(16),18(22)-tetramethylenedioxy-2,8,14,20-tetrapentyl resorcin[4]arene-5-yl}-3-methyl-1H-1,2,3-triazolium iodide (2), have been synthesized and assessed in the palladium-catalyzed Suzuki−Miyaura cross-coupling of aryl chlorides, with aryl boronic acids. As a general trend, the reaction rates obtained with 1 were significantly higher (up to 5 times) than those observed for 2, this mainly reflected a sterically more accessible metal center in the catalytic intermediates formed with 1. The presence of flexible pentyl chains in these intermediates, which might sterically interact with the metal center, when the latter adopts an exo-orientation with respect to the cavity, were likely responsible for the observed good performance

Proton Beam Therapy for Non-Small Cell Lung Cancer: Current Clinical Evidence and Future Directions

Lung cancer is the leading cancer cause of death in the United States. Radiotherapy is an essential component of the definitive treatment of early-stage and locally-advanced lung cancer, and the palliative treatment of metastatic lung cancer. Proton beam therapy (PBT), through its characteristic Bragg peak, has the potential to decrease the toxicity of radiotherapy, and, subsequently improve the therapeutic ratio. Herein, we provide a primer on the physics of proton beam therapy for lung cancer, present the existing data in early-stage and locally-advanced non-small cell lung cancer (NSCLC), as well as in special situations such as re-irradiation and post-operative radiation therapy. We then present the technical challenges, such as anatomic changes and motion management, and future directions for PBT in lung cancer, including pencil beam scanning