In vivo imaging of cellular proliferation in colorectal cancer using positron emission tomography

Background and aims: Positron emission tomography (PET) using 18F labelled 2-fluoro-2-deoxy-D-glucose (18FDG) is an established imaging tool, although the recent development of a biologically stable thymidine analogue [18F] 3'-deoxy-3-fluorothymidine (18FLT) has allowed PET to image cellular proliferation by utilising the salvage pathway of DNA synthesis. In this study, we have compared uptake of 18FLT and 18FDG with MIB-1 immunohistochemistry to evaluate the role of PET in quantifying in vivo cellular proliferation in colorectal cancer (CRC). Patients and methods: Patients with resectable, primary, or recurrent CRC were prospectively studied. Thirteen lesions from 10 patients (five males, five females), median age 68 years (range 54–87), were evaluated. Patients underwent 18FDG and 18FLT PET scanning. Tracer uptake within lesions was quantified using standardised uptake values (SUVs). Histopathological examination and MIB-1 immunohistochemistry were performed on all lesions, and proliferation quantified by calculating a labelling index (% of MIB-1 positively stained nuclei within 1500 tumour cells). Results: Histology confirmed adenocarcinoma in 12 of 13 lesions; the remaining lesion was reactive. All eight extrahepatic lesions were visualised using both 18FLT and 18FDG. Three of the five resected liver metastases were also avid for 18FLT and showed high proliferation, while the remaining two lesions which demonstrated no uptake of 18FLT had correspondingly very low proliferation. There was a statistically significant positive correlation (r =0.8, p<0.01) between SUVs of the tumours visualised with 18FLT and the corresponding MIB-1 labelling indices. No such correlation was demonstrated with 18FDG avid lesions (r =0.4). Conclusions: 18FLT PET correlates with cellular proliferation markers in both primary and metastatic CRC. This technique could provide a mechanism for in vivo grading of malignancy and early prediction of response to adjuvant chemotherapy

PIK3CA mutations in advanced cancers: characteristics and outcomes.

PIK3CA mutations are frequently diagnosed in diverse cancers and may predict response to PI3K/AKT/mTOR inhibitors. It remains unclear whether they are associated with other characteristics. We analyzed characteristics and outcome of 90 consecutive patients with diverse advanced tumors and PIK3CA mutations and 180 wild-type PIK3CA controls matched by tumor type, gender, and age referred to the Clinical Center for Targeted Therapy. PIK3CA and MAPK mutations (KRAS, NRAS, and BRAF) were analyzed using polymerase chain reaction-based DNA sequencing. The most frequent PIK3CA mutations were E545K (31/90, 34%), E542K (16/90, 18%) in exon 9, and H1047R (20/90, 22%) in exon 20. PIK3CA mutations compared to wild-type PIK3CA were associated with simultaneous KRAS (p=0.047) and MAPK mutations (p=0.03), but only MAPK mutations were confirmed as having an independent association in multivariate analysis. Rates of lung, bone, liver and brain metastases were similar in PIK3CA-mutant and wild-type patients. Patients with PIK3CA mutations treated on trials with PI3K/AKT/mTOR inhibitors had a higher partial/complete response (PR/CR) rate than wild-type PIK3CA patients treated with their best phase I therapy (10/56, 18% vs. 12/152, 8%; p=0.045), but not a prolonged progression-free survival. Patients with H1047R PIK3CA mutations had higher PR/CR rate with PI3K/AKT/mTOR inhibitors compared to wild-type PIK3CA patients treated with their best phase I therapy (6/16, 38% vs. 12/152, 8%; p=0.003). In conclusion, PIK3CA mutations in diverse cancers were not associated with clinical characteristics, but were correlated with MAPK mutations. PIK3CA mutations, especially, H1047R, were associated with attaining a PR/CR to PI3K/AKT/mTOR pathway inhibitors

ESR, raman and conductivity studies on fractionated poly(2-methoxyaniline-5-sulfonic acid)

Synthesis methods used to produce poly(2-methoxyaniline-5-sulfonic acid) (PMAS), a water soluble, self-doped conducting polymer, have been shown to form two distinctly different polymer fractions with molecular weights of approximately 2 kDa and 8 -10 kDa. The low molecular weight (LMWT) PMAS fraction is redox inactive and non-conducting while the high molecular weight (HMWT) PMAS is electro-active with electrical conductivities of 0.94 0.05 S cm-1. Previous investigations have illustrated the different photochemical and electrochemical properties of these fractions, but have not correlated these properties with the structural and electronic interactions that drive them. Incomplete purification of the PMAS mixture, typically via bag dialysis, has been shown to result in a mixture of approximately 50:50 HMWT:LMWT PMAS with electrical conductivity significantly lower at approximately 0.10 to 0.26 S cm-1. The difference between the electrical conductivities of these fractions has been investigated by the controlled addition of the non-conducting LMWT PMAS fraction into the HMWT PMAS composite film with the subsequent electronic properties investigated by solid-state ESR and Raman spectroscopies. These studies illustrate strong electronic intereactions of the insulating LMWT PMAS with the emeraldine salt HMWT PMAS to substantially alter the population of the electronic charge carriers in the conducting polymer. ESR studies on these mixtures, when compared to HMWT PMAS, exhibited a lower level of electron spin in the presence of LMWT PMAS indicative of the the formation of low spin bipolarons without a change the oxidation state of the conducting HMWT fraction

Topoisomerase II inhibitors induce DNA damage-dependent interferon responses circumventing Ebola virus immune evasion

Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinase-dependent manner and to also trigger the DNA-sensing cGAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication

The Interrelated Multifactorial Actions of Cortisol and Klotho: Potential Implications in the Pathogenesis of Parkinson's Disease.

The pathogenesis of Parkinson's disease (PD) is complex, multilayered, and not fully understood, resulting in a lack of effective disease-modifying treatments for this prevalent neurodegenerative condition. Symptoms of PD are heterogenous, including motor impairment as well as non-motor symptoms such as depression, cognitive impairment, and circadian disruption. Aging and stress are important risk factors for PD, leading us to explore pathways that may either accelerate or protect against cellular aging and the detrimental effects of stress. Cortisol is a much-studied hormone that can disrupt mitochondrial function and increase oxidative stress and neuroinflammation, which are recognized as key underlying disease mechanisms in PD. The more recently discovered klotho protein, considered a general aging-suppressor, has a similarly wide range of actions but in the opposite direction to cortisol: promoting mitochondrial function while reducing oxidative stress and inflammation. Both hormones also converge on pathways of vitamin D metabolism and insulin resistance, also implicated to play a role in PD. Interestingly, aging, stress and PD associate with an increase in cortisol and decrease in klotho, while physical exercise and certain genetic variations lead to a decrease in cortisol response and increased klotho. Here, we review the interrelated opposite actions of cortisol and klotho in the pathogenesis of PD. Together they impact powerful and divergent mechanisms that may go on to influence PD-related symptoms. Better understanding of these hormones in PD would facilitate the design of effective interventions that can simultaneously impact the multiple systems involved in the pathogenesis of PD

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE

Combined search for the quarks of a sequential fourth generation

Results are presented from a search for a fourth generation of quarks produced singly or in pairs in a data set corresponding to an integrated luminosity of 5 inverse femtobarns recorded by the CMS experiment at the LHC in 2011. A novel strategy has been developed for a combined search for quarks of the up and down type in decay channels with at least one isolated muon or electron. Limits on the mass of the fourth-generation quarks and the relevant Cabibbo-Kobayashi-Maskawa matrix elements are derived in the context of a simple extension of the standard model with a sequential fourth generation of fermions. The existence of mass-degenerate fourth-generation quarks with masses below 685 GeV is excluded at 95% confidence level for minimal off-diagonal mixing between the third- and the fourth-generation quarks. With a mass difference of 25 GeV between the quark masses, the obtained limit on the masses of the fourth-generation quarks shifts by about +/- 20 GeV. These results significantly reduce the allowed parameter space for a fourth generation of fermions.Comment: Replaced with published version. Added journal reference and DO

Dysfunctional uterine bleeding: ormeloxifene versus combined oral contraceptive pills

Background: Dysfunctional uterine bleeding is abnormal bleeding that occurs in the absence of recognizable pelvic pathology, general medical disease, or pregnancy.  Globally, health care systems are focusing on low morbidity and low cost therapeutic interventions. Hence, medical treatment for DUB is high on the priority list. This comparative study was conducted to analyse the efficacy of ormeloxifene and combined oral contraceptive pills in reducing the blood loss and endometrial thickness in cases of DUB.Methods: This prospective study was conducted on women with dysfunctional uterine bleeding, who attended Gynaecology OPD at Hind Institute of Medical Sciences, between August 2015 and April 2016. After applying inclusion and exclusion criteria, 72 women diagnosed with DUB were enrolled randomly in two groups A and B. Group A was treated by Ormeloxifene and Group B patients were treated with combined oral contraceptive pills for three consecutive cycles. The efficacies of the studied drugs were compared by analyzing the mean change in the pre and post treatment PBAC score, haemoglobin level and endometrial thickness using unpaired t-test.Results: Ormeloxifene was found to be significantly more effective (p <0.0001) than OCPs in controlling the menstrual blood loss (79% reduction in group A Vs 55.5% reduction in group B). Reduction in endometrial thickness was also more in the group receiving Ormrloxifene, however this was statistically not significant (p = 0.19). No major side effect observed with the use of Ormeloxifene.Conclusions: Ormeloxifene can be an effective and safe therapy in the treatment of Dysfunctional uterine bleeding