A phase II randomized trial of RAdium-223 dichloride and SABR Versus SABR for oligomEtastatic prostate caNcerS (RAVENS).

BACKGROUND: Metastasis directed therapy (MDT) for patients with oligometastatic disease is associated with improvements in progression free survival (PFS) and overall survival (OS) compared to systemic therapy alone. Additionally, within a prostate-cancer-specific cohort, MDT is able to forestall initiation of androgen deprivation therapy (ADT) in men with hormone-sensitive, oligometastatic prostate cancer (HSOPCa) compared to observation. While MDT appears to be safe and effective in HSOPCa, a large percentage of men will eventually have disease recurrence. Patterns of failure in HSOPCa demonstrate patients tend to have recurrence in the bone following MDT, raising the question of sub-clinically-apparent osseous disease. Radium-223 dichloride is a radiopharmaceutical with structural similarity to calcium, allowing it to be taken up by bone where it emits alpha particles, and therefore might have utility in the treatment of micrometastatic osseous disease. Therefore, the primary goal of the phase II RAVENS trial is to evaluate the efficacy of MDT + radium-223 dichloride in prolonging progression free survival in men with HSOPCa. METHODS: Patients with HSOPCa and 3 or less metastases with at least 1 bone metastasis will be randomized 1:1 to stereotactic ablative radiation (SABR, also known as stereotactic body radiation therapy (SBRT)) alone vs SABR + radium-223 dichloride with a minimization algorithm to balance assignment by institution, primary intervention, prior hormonal therapy, and PSA doubling time. SABR is delivered in one to five fractions and patients in the SABR + radium-223 dichloride arm will receive six infusions of radium-223 dichloride at four-week intervals. The primary end point is progression free survival. The secondary clinical endpoints include toxicity and quality of life assessments, local control at 12 months, locoregional progression, time to distant progression, time to new metastasis, and duration of response. DISCUSSION: The RAVENS trial will be the first described phase II, non-blinded, randomized study to compare SABR +/- radium-223 dichloride in patients with HSOPCa and 3 or less metastases with at least one bone metastasis. The primary hypothesis is that SABR + radium-223 dichloride will increase median progression-free survival from 10 months in the SABR arm to 20 months in the SABR + radium-223 dichloride arm. TRIAL REGISTRATIONS: Clinicaltrials.gov. Identifier: NCT04037358. Date of Registration: July 30, 2019. Date of First Participant Enrolled: August 9, 2019. Date of Last Approved Amendment: October 16, 2019. Protocol Version: Version 5.

Follow-Up of Side Effects throughout the Entire Course of Coronavirus Vaccination.

Vaccines are considered the best protective means against coronavirus infection. There is increasing interest in reporting the side effects of vaccines, especially for individuals younger than 18 years old. Accordingly, this analytical cohort study aims to report on the side effects of adult and young individuals who received vaccination within 24 h, 72 h, 5 days, and 1 week through the entire course of vaccination (ECoV). A validated online survey was used to collect information. In total, 1069 individuals were completely followed. Most individuals received the Pfizer vaccine (59.6%). Most individuals had received two doses (69.4%). Very strong and statistically significant associations with side effects (p < 0.05, Phi (Φ) > 0.25) throughout the ECoV were reported for the type of vaccine and female gender. Non-smokers reported weak statistically significant associations. Fatigue and localized pain were the most commonly reported side effect, with onset within 24 h and duration of less than 72 h. The prevalence of reported side effects was statistically significantly higher among young individuals (<18 years old) than among adults (X2 (1) =7.6, p = 0.006. Phi φ = 0.11).

Effects of mammary cancer and chemotherapy on neuroimmunological markers and memory function in a preclinical mouse model.

Treatment modalities for breast cancer, including cyclophosphamide chemotherapy, have been associated with the development of cognitive decline (CRCD), which is characterized by impairments in memory, concentration, attention, and executive functions. We and others have identified a link between inflammation and decreased cognitive performance in patients with breast cancer receiving chemotherapy. In order to better understand the inflammation-associated molecular changes within the brain related to tumor alone or in combination with chemotherapy, we orthotopically implanted mouse mammary tumors (E0771) into female C57BL/6 mice and administered clinically relevant doses of cyclophosphamide and doxorubicin intravenously at weekly intervals for four weeks. We measured serum cytokines and markers of neuroinflammation at 48 h and up to one month post-treatment and tested memory using a reward-based delayed spatial alternation paradigm. We found that breast tumors and chemotherapy altered systemic inflammation and neuroinflammation. We further found that the presence of tumor and chemotherapy led to a decline in memory over time at the longest delay, when memory was the most taxed, compared to shorter delay times. These findings in a clinically relevant mouse model shed light on possible biomarkers for CRCD and add to the growing evidence that anti-inflammatory strategies have the potential to mitigate cancer- or treatment-related side effects.

The Role of Mechanically-Activated Ion Channels Piezo1, Piezo2, and TRPV4 in Chondrocyte Mechanotransduction and Mechano-Therapeutics for Osteoarthritis.

Mechanical factors play critical roles in the pathogenesis of joint disorders like osteoarthritis (OA), a prevalent progressive degenerative joint disease that causes debilitating pain. Chondrocytes in the cartilage are responsible for extracellular matrix (ECM) turnover, and mechanical stimuli heavily influence cartilage maintenance, degeneration, and regeneration via mechanotransduction of chondrocytes. Thus, understanding the disease-associated mechanotransduction mechanisms can shed light on developing effective therapeutic strategies for OA through targeting mechanotransducers to halt progressive cartilage degeneration. Mechanosensitive Ca2+-permeating channels are robustly expressed in primary articular chondrocytes and trigger force-dependent cartilage remodeling and injury responses. This review discusses the current understanding of the roles of Piezo1, Piezo2, and TRPV4 mechanosensitive ion channels in cartilage health and disease with a highlight on the potential mechanotheraputic strategies to target these channels and prevent cartilage degeneration associated with OA.

Resistance for anti-tuberculosis drugs in central Black Sea region of Turkey.

One of the primary aims in tuberculosis (TB) management is to detect new cases as early as possible, and instigate the most appropriate therapy, for which it is important to know the characteristics of TB drug resistance in society. The aim of our study was to determine the resistance status of tuberculosis in the Samsun region of Turkey. To achieve that, the medical records of 1,029 pulmonary tuberculosis patients admitted to Samsun Chest Diseases and Chest Surgery Hospital between 2004 and 2006 were analyzed for drug resistance characteristics. In order to define the problem, isolates were tested on Lowenstein-Jensen medium. For drug susceptibility testing, isoniazid (I), streptomycin (S), ethambutol (E), rifampicin (R) and the radiometric Bactec 460 TB system were used. Eighty-six percent (86%) of the cases (623/721) were new patients, and 13.5% (98/721) were previously treated cases. One hundred and thirty-four (134) of the 721 patients (18.6%) had resistance to one or more drugs. Resistance to any drug was determined in 16.9% (105/623) cases of new patients. I resistance was 13.2%, any R resistance was 2.9%, and multi-drug resistance (MDR) was 1.9%. In previously treated cases, resistance to any drug was 29.6%, any I resistance was 26.5%, any R resistance was 15.3%, and MDR was 13.3%. It was concluded that resistance to anti-tuberculosis drugs is an important problem in Samsun.

Anti-diabetic study of vitamin B6 on hyperglycaemia induced protein carbonylation, DNA damage and ROS production in alloxan induced diabetic rats.

Oxidative stress performs an imperative role in the onset and progression of diabetes. Metabolic enzymes and cellular organelles are detrimental to increased levels of free radicals and the subsequent reduction in anti-oxidant defence. Pyridoxamine (vitamin B6) is an indispensible nutrient for humans and is considered to be an important food additive too. The aim of this research was to examine the effect of vitamin B6 in a diabetic environment. This study reports the effects of pyridoxamine supplementation in alloxan induced diabetic rats. Diabetes was induced by the single intra peritoneal dose of alloxan (120 mg per kg body weight). Diabetic rats were treated with pyridoxamine (10 and 15 mg per kg body weight) and compared with a control set of diabetic rats without supplementation. Pyridoxamine treatment showed dose dependent recovery in all parameters. A notable decline in oxidative stress parameters and ROS production with reductions in fasting blood glucose levels along with normal patterns of the glucose tolerance test has been reported here. Histological studies reveal damage recovery in the liver as well as kidney tissues. A notable amount of recovery was observed in cellular DNA distortion and damage. It is thus advocated that pyridoxamine might help in reducing problems associated with diabetes. A probable mechanism pertaining to the action of pyridoxamine is proposed as well.

Glyoxal Induced Transition of Transferrin to Aggregates: Spectroscopic, Microscopic and Molecular Docking Insight.

BACKGROUND & OBJECTIVE: The present study was aimed at characterizing the conformational alterations induced in human transferrin, the iron regulatory protein by glyoxal. Since protein aggregation is at the core of many disorders, thus interest in this domain has increased significantly during the past years. METHODS: In our present study, the effect of glyoxal was monitored on human transferrin using multispectroscopic and multi-microscopic studies. RESULTS: Intrinsic fluorescence spectroscopy suggested changes in native conformation of human transferrin evident by decreased fluorescence and blue shift in the presence of glyoxal. Further, extrinsic fluorescence was retorted and the results showed the formation of aggregates; apparent by increased Congo red (CR) absorbance, Thioflavin T (ThT) and ANS fluorescence and TEM of human transferrin in the presence of glyoxal. Molecular docking was also employed to see which residues are at core of human transferrin and glyoxal interaction. Reactive oxygen species (ROS) generation assays revealed enhanced ROS levels by human transferrin after treatment with glyoxal. CONCLUSION: Thus, our study proposes that glyoxal induces the formation of aggregates in human transferrin. These aggregates further generate ROS which are key players in the complications associated with diabetes mellitus, giving our study clinical perspective.

Study of pyridoxamine against glycation and reactive oxygen species production in human serum albumin as model protein: An in vitro & ex vivo approach.

Hyperglycaemia is considered to be a driving factor for advanced glycated end products (AGEs). Inhibiting the process of glycation play an important role in reducing the diabetes related complications. We have explored the glucose mediated glycation and antiglycation activity of pyridoxamine using human serum albumin (HSA). Protein was incubated with glucose for 28 days at physiological temperature to achieve glycation. Antiglycation activity was assessed by the estimation of carbonyl content, free lysine and AGE specific fluorescence. Molecular docking was used to study the interaction of pyridoxamine with HSA and to get a detailed understanding of binding sites and binding energy. Glycation was reduced by pyridoxamine to commendable levels which was evident by the quantification of free lysine and carbonyl content. Pyridoxamine treatment also prevented the loss in secondary structure induced by glycation. It has also emerged as the quencher of reactive oxygen species which lead to the protection of DNA from oxidative damage. Pyridoxamine was found to be located at subdomain IIA of HSA with binding energy of -5.6 kcal/mol. These results are high points in the antiglycation activity of pyridoxamine. Its antioxidant nature and antiglycation activity are proof of its potential in preventing disease progression in diabetes.