New orally active DNA minor groove binding small molecule CT-1 acts against breast cancer by targeting tumor DNA damage leading to p53-dependent apoptosis.

Targeting tumor DNA damage and p53 pathway is a clinically established strategy in the development of cancer chemotherapeutics. Majority of anti-cancer drugs are delivered through parenteral route for reasons like severe toxicity, lack of stability, and poor enteral absorption. Current DNA targeting drugs in clinical like anthracycline suffers from major drawbacks like cardiotoxicity. Here, we report identification of a new orally active small molecule curcumin-triazole conjugate (CT-1) with significant anti-breast cancer activity in vitro and in vivo. CT-1 selectively and significantly inhibits viability of breast cancer cell lines; retards cells cycle progression at S phase and induce mitochondrial-mediated cell apoptosis. CT-1 selectively binds to minor groove of DNA and induces DNA damage leading to increase in p53 along with decrease in its ubiquitination. Inhibition of p53 with pharmacological inhibitor as well as siRNA revealed the necessity of p53 in CT-1-mediated anti-cancer effects in breast cancer cells. Studies using several other intact p53 and deficient p53 cancer cell lines further confirmed necessity of p53 in CT-1-mediated anti-cancer response. Pharmacological inhibition of pan-caspase showed CT-1 induces caspase-dependent cell death in breast cancer cells. Most interestingly, oral administration of CT-1 induces significant inhibition of tumor growth in LA-7 syngeneic orthotropic rat mammary tumor model. CT-1 treated mammary tumor shows enhancement in DNA damage, p53 upregulation, and apoptosis. Collectively, CT-1 exhibits potent anti-cancer effect both in vitro and in vivo and could serve as a safe orally active lead for anti-cancer drug development. © 2016 Wiley Periodicals, Inc.

Theophylline, a methylxanthine drug induces osteopenia and alters calciotropic hormones, and prophylactic vitamin D treatment protects against these changes in rats.

The drug, theophylline is frequently used as an additive to medications for people suffering from chronic obstructive pulmonary diseases (COPD). We studied the effect of theophylline in bone cells, skeleton and parameters related to systemic calcium homeostasis. Theophylline induced osteoblast apoptosis by increasing reactive oxygen species production that was caused by increased cAMP production. Bone marrow levels of theophylline were higher than its serum levels, indicating skeletal accumulation of this drug. When adult Sprague-Dawley rats were treated with theophylline, bone regeneration at fracture site was diminished compared with control. Theophylline treatment resulted in a time-dependent (at 4- and 8 weeks) bone loss. At 8 weeks, a significant loss of bone mass and deterioration of microarchitecture occurred and the severity was comparable to methylprednisone. Theophylline caused formation of hypomineralized osteoid and increased osteoclast number and surface. Serum bone resorption and formation marker were respectively higher and lower in the theophylline group compared with control. Bone strength was reduced by theophylline treatment. After 8 weeks, serum 25-D3 and liver 25-hydroxylases were decreased in theophylline group than control. Further, theophylline treatment reduced serum 1, 25-(OH)2 vitamin D3 (1,25-D3), and increased parathyroid hormone and fibroblast growth factor-23. Theophylline treated rats had normal serum calcium and phosphate but displayed calciuria and phosphaturia. Co-administration of 25-D3 with theophylline completely abrogated theophylline-induced osteopenia and alterations in calcium homeostasis. In addition, 1,25-D3 protected osteoblasts from theophylline-induced apoptosis and the attendant oxidative stress. We conclude that theophylline has detrimental effects in bone and prophylactic vitamin D supplementation to subjects taking theophylline could be osteoprotective.

Postoperative oncological referral patterns for adjuvant treatment of patients undergoing curative resections for non-small-cell lung cancer at a regional thoracic centre.

OBJECTIVE: The Heartlands hospital provides services for 13 hospitals in the Pan Birmingham, Three Counties and Arden Lung Cancer Networks. After surgery for lung cancer, patients may be referred for adjuvant chemotherapy. The referral patterns and follow-up of patients differ between the various trusts. This study examines the current referral patterns following surgery with a view to identify areas for improvement. METHODS: We performed a retrospective review of 115 patients who underwent curative anatomical resection between April 2006 and March 2007. We reviewed the patient's progress following discharge from the surgeons at various defined points, including discussion at a multidisciplinary team (MDT) meeting following surgery, referral to oncologist, oncology treatment acceptance and adjuvant treatment completion. RESULTS: Of the 115 patients, four patients died after surgery. The demographics of the surviving 111 patients mirrored the national trends with the average age being 69+9.6 years. The predominant tumours were adenocarcinomas (44.1%) and squamous cell cancers (44.1%). A total of 82 patients were discussed in an MDT meeting and a further 16 patients were directly referred to the oncologists for consideration for chemotherapy. As many as 67 patients were referred for chemotherapy. Forty-eight patients were offered chemotherapy, 38 patients accepted and 25 of them completed the chemotherapy. Thirteen patients could not complete due to drug toxicity. Data collection for the study highlighted organisational problems with data collection and non-uniformity in the role of the lung cancer co-ordinators. The postoperative management of stage I lung cancer patients varied between the units. CONCLUSIONS: This study highlights areas of improvement in the current patient pathway for postoperative patients following lung cancer surgery and stresses the importance of achieving a consensus with regard to the management of resectable lung cancer. A method of data collection that is accurate, easily accessible and complete is recommended to help in future auditing of patient outcomes and help in improvement of services.

Bidirectional telemetry controller for neuroprosthetic devices.

We present versatile multifunctional programmable controller with bidirectional data telemetry, implemented using existing commercial microchips and standard Bluetooth protocol, which adds convenience, reliability, and ease-of-use to neuroprosthetic devices. Controller, weighing 190 g, is placed on animal's back and provides bidirectional sustained telemetry rate of 500 kb/s , allowing real-time control of stimulation parameters and viewing of acquired data. In continuously-active state, controller consumes approximately 420 mW and operates without recharge for 8 h . It features independent 16-channel current-controlled stimulation, allowing current steering; customizable stimulus current waveforms; recording of stimulus voltage waveforms and evoked neuronal responses with stimulus artifact blanking circuitry. Flexibility, scalability, cost-efficiency, and a user-friendly computer interface of this device allow use in animal testing for variety of neuroprosthetic applications. Initial testing of the controller has been done in a feline model of brainstem auditory prosthesis. In this model, the electrical stimulation is applied to the array of microelectrodes implanted in the ventral cochlear nucleus, while the evoked neuronal activity was recorded with the electrode implanted in the contralateral inferior colliculus. Stimulus voltage waveforms to monitor the access impedance of the electrodes were acquired at the rate of 312 kilosamples/s. Evoked neuronal activity in the inferior colliculus was recorded after the blanking (transient silencing) of the recording amplifier during the stimulus pulse, allowing the detection of neuronal responses within 100 mus after the end of the stimulus pulse applied in the cochlear nucleus.

An indigenous approach to manage the osteoarthritis of knee joint with lakshadi guggulu, kalka-patra bandhan and knee traction.

The clinical study was attempted to develop a holistic treatment module for the patients of osteoarthritis of the knee. The study was done in 10 patients of Osteoarthritis of knee. The patients were given Lakshadi Guggulu Tablet, Kalka patra -bandhan ( Bandage of medicinal paste) and Knee joint traction. The duration of treatment was 1 month with follow every week. At the end of 4 weeks, statistically significant results were found in the criteria of assessment specifically in severity of pain, deep grading of tenderness, walking distance and movement of knee joint(degree of flexion). Maximum response was observed in the deep grading of tenderness (76%). The combined therapy with Lakshadi .Guggulu, Kalka bandhan and traction therapy in the management of OA of the knee joint was very effective. It is essential to evaluate the clinical efficacy of this combination in a large population.

The spermicidal and antitrichomonas activities of SSRI antidepressants.

The study investigated spermicidal and antitrichomonas activities of selective serotonin reuptake inhibitor (SSRI) antidepressants with a view to generate new lead for development of dual-function spermicidal microbicides, which is an urgent global need. Fluoxetine, Sertraline, and Fluvoxamine exhibited both spermicidal and anti-STI (antitrichomonas) activities in vitro, whereas Paroxetine and Citalopram showed only the spermicidal activity. Fluoxetine exhibited better activity profile than the other antidepressant drugs with its spermicidal and antitrichomonas activities being comparable to that of the OTC contraceptive Nonoxynol-9. The non-detergent nature of Fluoxetine and a much lower spermicidal ED50 value (than N-9) may add considerably to its merit as a candidate for microbicidal contraceptive. Thus, the antidepressants exhibiting both spermicidal and antitrichomonas activities might provide useful lead for the development of novel, dual-function spermicidal contraceptives.