Absence of 3a0 charge density wave order in the infinite-layer nickelate NdNiO2.

A hallmark of many unconventional superconductors is the presence of many-body interactions that give rise to broken-symmetry states intertwined with superconductivity. Recent resonant soft X-ray scattering experiments report commensurate 3a0 charge density wave order in infinite-layer nickelates, which has important implications regarding the universal interplay between charge order and superconductivity in both cuprates and nickelates. Here we present X-ray scattering and spectroscopy measurements on a series of NdNiO2+x samples, which reveal that the signatures of charge density wave order are absent in fully reduced, single-phase NdNiO2. The 3a0 superlattice peak instead originates from a partially reduced impurity phase where excess apical oxygens form ordered rows with three-unit-cell periodicity. The absence of any observable charge density wave order in NdNiO2 highlights a crucial difference between the phase diagrams of cuprate and nickelate superconductors.

Emerging autophagic endo-lysosomal targets in the management of Parkinson's disease.

Synucleopathies, specifically Parkinson's disease, are still incurable and available therapeutic options are scarce and symptomatic. The autophagy-lysosomal-endosomal system is an indigenous mechanism to manage the proteome. Excess/misfolded protein accumulation activates this system, which degrades the undesired proteins via lysosomes. Cells also eliminate these proteins by releasing them into the extracellular space via exosomes. However, the sutophagy-lysosomal-endosomal system becomes unfunctional in Parkinson's disease and there is accumulation and spread of pathogenic alpha-synuclein. Neuronal degeneration results Owing to pathogenic alpha-synuclein. Thus, the autophagy-lysosomal-endosomal system could be a promising target for neuroprotection. In the present review, we discuss the autophagy-lysosomal-endosomal system as an emerging target for the management of Parkinson's disease. Modulation of these targets associated with the autophagy-lysosomal-endosomal system can aid in clearing pathogenic alpha-synuclein and prevent the degeneration of neurons.

Combating colorectal cancer with immunotherapy: Where are we?

Despite incessant advancement in the therapeutic regimens against colorectal cancer (CRC), treatment failure, metastasis and serious side effects associated with the available therapeutic options demand specific targeted therapies that could help in improving the survival rate with significantly less toxicity, fewer untoward effects and improved efficacy. In-depth studies highlighted the potential of CRC to be immune-responsive, thereby opening a new door in the development of strategies to combat CRC. Immunotherapy has attracted a myriad of researchers with a hope that it could potentially increase the efficacy of the treatment regimens in parallel to the reduction of toxicity. Colorectal tumors undergo immune evasion, suppressing patients' immunity and making them susceptible to infections. Therefore, a viable option could be stimulating a patient's own immune system with the help of immune modulators to fight against CRC. This review briefly discusses the immune responsiveness of CRC as well as tumor-associated antigens in CRC, and highlights the current endeavors of the scientific community in the field of immune modulators against CRC that are under development including varied types of vaccines, checkpoint inhibitors and adoptive T-cell therapy.

Experience of Definitive Chemoradiation for Oesophageal Cancer Within a Large Regional Cancer Treatment Centre: Improving Outcomes and Tolerability.

AIMS: To review delivery of definitive chemoradiation (dCRT) for patients with oesophageal cancer within a large regional cancer centre. To assess toxicity, tolerability and outcomes and compare with published data. MATERIALS AND METHODS: A retrospective review of patients undergoing dCRT between November 2009 and November 2014 was carried out. Data were collected regarding treatment completion, radiotherapy plans, toxicity, failure and death. Kaplan-Meier survival curves with a Log-rank test for significance were used for survival analysis. RESULTS: In total, 179 patients were analysed. The median age at diagnosis was 70 years. Forty-four (24.6%) patients had T1 or T2 tumours, 113 (63.1%) T3 and 18 (10.1%) T4; 117 (65.4%) patients were node positive on initial staging. One hundred and forty patients were treated before 2012 with CRT and two adjuvant cycles of cisplatin and capecitabine. Of these, only 50% completed both adjuvant cycles of chemotherapy. Thirty-nine patients were treated after 2012 with neoadjuvant cisplatin and capecitabine followed by CRT. Of these, 92% completed all planned chemotherapy. Ninety-five per cent of patients completed radiotherapy without interruption, but only 46% completed concurrent capecitabine. The mean planning target volume (PTV) length was 13 cm (range 6.9-22.2 cm) and 27 (15%) patients had a PTV length greater than 16 cm. After a median follow-up of 19.6 months (range 3.0-71.9), 83 patients (46%) had relapsed, with 43 (24%) patients having isolated locoregional recurrence. The median overall survival was 26 months (95% confidence interval 20.2-31.8) with a 5 year overall survival rate of 19.7% (95% confidence interval 10.4-31.2). CONCLUSIONS: Our series shows comparable survival rates with published data despite an unselected population. The transition to neoadjuvant chemotherapy before CRT has improved tolerability and increased rates of completion of treatment. The locoregional failure rate remains significant and strategies for improving this, such as changing the chemotherapy back bone and radiation dose escalation, are eagerly awaited within the SCOPE-2 study.

Recent advances in clinical development of leukotriene B4 pathway drugs.

The LTB4 pathway is an attractive target for therapeutic drug development. Two broad classes of drugs have been pursued: antagonists of the primary LTB4 receptors (BLT1 and BLT2) and inhibitors of LTA4 Hydrolase (LTA4H), the rate limiting enzyme in the production of LTB4. An initial wave of effort culminated in the 1990s. Over the past 15 years, a second wave of more selective drug candidates, including at least 5 BLT antagonists and 6 LTA4H inhibitors, have reached Phase 2 clinical trials. Despite the extensive efforts to discover and develop LTB4 pathway targeting drugs, only one has reached the market to date. Recently discovered complexities in the pathway and challenges in matching pathway intervention with therapeutic effect could explain the limited clinical success of LTB4 pathway drugs, even though there is a large body of scientific evidence linking LTB4 to human diseases and demonstrating efficacy of these compounds in a wide array of preclinical models. Herein, we describe the clinical programs for the most prominent recent examples from each broad class and discuss the clinical outcomes and their implications for future development of LTB4 pathway drugs.

Phase I Studies of Acebilustat: Pharmacokinetics, Pharmacodynamics, Food Effect, and CYP3A Induction.

Acebilustat is a new once-daily oral antiinflammatory drug in development for treatment of cystic fibrosis (CF) and other diseases. It is an inhibitor of leukotriene A4 hydrolase; therefore, production of leukotriene B4 (LTB4) in biological fluids provides a direct measure of the pharmacodynamic (PD) response to acebilustat treatment. Here we compare the pharmacokinetics (PK) and PD between CF patients and healthy volunteers, and investigate the food effect and CYP3A4 induction in healthy volunteers. No significant differences between study populations were observed for peak plasma level (Cmax ) or exposure (AUC). In healthy volunteers, a shift in time to Cmax (Tmax ) was observed after a high-fat meal, but there was no change in AUC. LTB4 production was reduced in the blood of both populations and in sputum from CF patients. Acebilustat did not induce CYP3A4. These results support continued clinical study of once-daily oral acebilustat in CF at doses of 50 and 100 mg.

Efficacy of nobiletin, a citrus flavonoid, in the treatment of the cardiovascular dysfunction of diabetes in rats.

Hyperglycemia induced oxidative stress is a prime factor for cardiovascular dysfunction (CVD) in diabetic patients. In this process matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) play important roles. Nobiletin, a polymethoxy citrus flavone, has potent MMP-2 and MMP-9 inhibitory activity in addition to antioxidant activity. We hypothesized that nobiletin due to its MMP-2 & MMP-9 inhibitory and antioxidant effects may ameliorate the cardiovascular dysfunction of diabetes. Diabetes was induced using streptozotocin (50 mg kg(-1) i.p.) in male wistar rats. Four weeks after the induction of diabetes, the rats were treated with nobiletin (10 mg kg(-1), and 25 mg kg(-1)) for a period of the following four weeks. At the end of eight weeks, hemodynamic parameters were recorded, cardiac hypertrophy was measured, and antioxidant assays, and gelatin zymography for MMP-2 & MMP-9 analysis and histopathology were performed. The vascular reactivity of the aorta was measured by recording the contractile response to phenylephrine and relaxation responses to acetylcholine. Treatment with 25 mg kg(-1) nobiletin ameliorated the hemodynamic parameters, oxidative stress, collagen level, MMP-2 and MMP-9 levels, and vascular reactivity significantly compared with vehicle treated diabetic group. Thus, this study suggests that nobiletin ameliorates the CVD of diabetes by inhibiting oxidative stress, MMP-2 & MMP-9 and can be used as a potential therapeutic approach.

Intraluminal high-dose-rate brachytherapy for palliation of dysphagia in cancer of the esophagus: initial experience at a single UK center.

Esophageal cancer tends to present with advanced disease, and the majority of patients are suitable only for palliative treatment at diagnosis. Dysphagia is the most common presenting symptom and significantly undermines quality of life. High-dose-rate intraluminal brachytherapy (ILBT) has been an option for the palliation of dysphagia for many years and has been used at our center since 2006. Experience was presented in terms of improvement of dysphagia and survival. Patients were identified from the local radiotherapy database. Original treatment sheets and clinical notes were reviewed retrospectively to obtain treatment details, pretreatment and post-treatment dysphagia scores, and survival information. Between January 2006 and January 2010, 21 patients of median age 77 years with a mean pretreatment dysphagia score of 2.5 underwent ILBT for esophageal cancer. All received 12 Gy in a single fraction. Thirteen (62%) had adenocarcinoma and eight (38%) squamous cell carcinoma. Four (19%) tumors were in the mid-esophagus and 17 (81%) in the lower esophagus. Eight had extension of tumor into the gastroesophageal junction. Seven patients (33%) received chemotherapy as first-line treatment prior to brachytherapy. Nineteen patients had clear documentation of dysphagia scores both pretreatment and post-treatment, and the improvement overall was significant (P= 0.04). Ten patients (53%) had an improvement in dysphagia score. Five of these (50%) went on to require further endoscopic intervention due to disease progression. Median duration of response was 4 months. Of the nonresponders, six (67%) went on to require further endoscopic intervention. No patients experienced documented toxicity aside from a short-lived acute esophagitis. Median survival from date of diagnosis was 12 months and from treatment date was 5 months (1-32 months). In our series of elderly patients with significant dysphagia, ILBT was a well-tolerated and effective treatment. It should be considered as a palliative option in esophageal cancer.

A therapeutic approach to treat cardiovascular dysfunction of diabetes.

Diabetes greatly increases risk of cardiovascular dysfunction and interruptions of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) have been shown to reduce the risk by alteration in extracellular matrix. We hypothesized that minocycline induced MMP-2 and MMP-9 inhibition can be enhanced by aspirin (through its COX and tPA inhibitory action) and this combination can reduce cardiovascular dysfunction of diabetes. Four weeks after diabetes induction (streptozotocin, 55 mg/kg, i.p.), rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of next four weeks. At the end of eighth week arterial pressure, heart rate and left ventricular pressure were recorded. Contractile response to phenylephrine (10(-5) M) and relaxation responses to acetylcholine (10(-9)-10(-4) M) were obtained from aortic rings of diabetic rats. Gel zymography was performed to evaluate MMP-2 and MMP-9 levels. Heart rate, mean arterial pressure, dp/dt(max) and dp/dt(min) were found significantly decreased in STZ diabetic rats when compared with normoglycemic group. Treatment with combination of minocycline and aspirin significantly ameliorate these compared to vehicle treated diabetic group. Endothelium-dependent relaxation responses induced by acetylcholine were decreased in diabetic rats and significantly higher in combination treated group. Collagen, MMP-2 and MMP-9 levels were significantly decreased in combined treated group when compared with diabetic control. Present study revealed that aspirin potentate minocycline induced MMP-2 and MMP-9 inhibition to ameliorate cardiovascular dysfunction of diabetes and this combination can be an approach for the treatment.

Minocycline with aspirin: a therapeutic approach in the treatment of diabetic neuropathy.

Enhanced production of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in diabetes leads to degradation of extracellular matrix in blood vessels and leads to complications of diabetes. In the present study, we have targeted MMP-2 and MMP-9 overactivation in diabetic neuropathy using a known MMP-2 and MMP-9 inhibitor, minocycline, with a non-selective COX inhibitor, aspirin. Streptozotocin-induced diabetic neuropathy was carried out in male Wistar rats and monitored by measuring the sensory nerve conduction velocity (SNCV), motor nerve conduction velocity (MNCV), tail flick latency and hot plate latency. Three weeks of treatment with a combination of minocycline and aspirin showed significant improvement in SNCV, MNCV, hot plate latency and tail flick latency when compared with diabetic control. The results of the present study suggest that MMP-2 and MMP-9 inhibition in the presence of COX inhibitor prevents the development of experimental diabetic neuropathy in rats and can be a potential approach for the treatment.

Use of imatinib mesylate in gastrointestinal stromal tumours: Pan-Birmingham Cancer Network experience.

AIMS: Imatinib mesylate, a selective tyrosine kinase receptor inhibitor of KIT and PDGFRalpha, is currently licensed for the treatment of unresectable or metastatic gastrointestinal stromal tumours (GISTs), which are KIT positive. Partial response rates in 65% of patients and stable disease in 20% of patients are typically seen. The aim of this study was to assess the effectiveness and toxicity of an unselected cohort of patients treated with imatinib mesylate and to compare these results with published data. MATERIALS AND METHODS: A retrospective audit of the use of imatinib mesylate in GISTs within the Pan-Birmingham Cancer Network was carried out. In total, 39 patients were identified, the first commenced imatinib mesylate in September 2001. RESULTS: The most common primary tumour sites were small intestine (19 [49%]) and stomach (12 [31%]). Initial curative resection was carried out in 21 (54%), palliative resection in three (8%) and 15 (38%) were unresectable. Of those who had curative resection, the median time to recurrence was 13 months (range 2-276). Common sites of metastases were liver (19 [49%]) and peritoneum (12 [31%]). At 24 months 70% remained on imatinib. A partial response was reported in 23 (59%), stable disease in seven (18%) and disease progression in four (10%). Five patients (13%) have yet to be reassessed at 3 months. Imatinib was well tolerated with minor side-effects; peri-orbital oedema (nine [23%]), skin rash (four [10%]), minor gastrointestinal bleed (one [3%]). No significant toxicity was documented in 18 (46%). CONCLUSIONS: The response rates achieved in this unselected cohort of patients are consistent with published data. The duration of tumour control is good, with most patients responding to imatinib mesylate for more than 2 years. Side-effects are mild and acceptable.

The potential role of serum CA 125 in an ultrasound-based screening program for familial ovarian cancer.

We have assessed the potential role of a test based upon the measurement of serum CA 125 in an ultrasound-based screening program for familial ovarian cancer. A sample of peripheral blood was taken from 1502 self-referred, asymptomatic women whose pedigree showed that at least one close relative had developed the disease. All women in the study underwent one screening by transvaginal ultrasonography (consisting of one or more scans) to detect any persistent lesion and a change in ovarian volume. Women with a positive result were referred for surgery. The concentration of serum CA 125 was measured in all samples at the end of the study. Seven ovarian cancers (4 invasive and 3 of borderline malignancy; 5 FIGO stage Ia, 1 stage IIa, 1 stage III) and 55 benign lesions were detected. We calculated the effect that a prescreening test (based on different threshold values for serum CA 125) would have had on the number of women entering the ultrasound-based screening program, and on the detection rate and false-positive rate of the overall procedure. There was a direct relationship between the number of women referred for ultrasound screening and the detection rate. The use of a threshold value for serum CA 125 > or = 20 U/ml would have meant that 380 women (25.3%) were referred for ultrasonography and 5 out of 7 cancers (71%) would have been detected with a false-positive rate of 1.1%. The odds of a woman with a positive screening result having cancer at surgery would have been about 1:3 (which would improve to about 1:1 if observational indices of color Doppler imaging and a morphological score had been used throughout). We concluded that a prescreening immunochemical test based on the measurement of serum CA 125 (with a threshold value of > or = 20 U/ml) would increase the prior odds for familial ovarian cancer by 2.8, but would lower the overall detection rate by 29% at the prevalence screening.