Engineered lignocellulosic based biochar to remove endocrine-disrupting chemicals: Assessment of binding mechanism.

The safety and health of aquatic organisms and humans are threatened by the increasing presence of pollutants in the environment. Endocrine disrupting chemicals are common pollutants which affect the function of endocrine and causes adverse effects on human health. These chemicals can disrupt metabolic processes by interacting with hormone receptors upon consumptions by humans or aquatic species. Several studies have reported the presence of endocrine disrupting chemicals in waterbodies, food, air and soil. These chemicals are associated with increasing occurrence of obesity, metabolic disorders, reproductive abnormalities, autism, cancer, epigenetic variation and cardiovascular risk. Conventional treatment processes are expensive, not environment friendly and unable to achieve complete removal of these harmful chemicals. In recent years, biochar from different sources has gained a considerable interest due to their adsorption efficiency with porous structure and large surface areas. biochar derived from lignocellulosic biomass are widely used as sustainable catalysts in soil remediation, carbon sequestration, removal of organic and inorganic pollutants and wastewater treatment. This review conceptualizes the production techniques of biochar from lignocellulosic biomass and explores the functionalization and interaction of biochar with endocrine-disrupting chemicals. This review also identifies the further needs of research. Overall, the environmental and health risks of endocrine-disrupting chemicals can be dealt with by biochar produced from lignocellulosic biomass as a sustainable and prominent approach.

Echocardiography for Volume Assessment in Acute Myocardial Infarction.

Background Errors caused by improper volume estimation increase acute mortality rates in acute myocardial infarction (AMI). We aimed to determine volume status in AMI patients using echocardiography and to correlate the findings with clinical outcomes. Methods This cross-sectional, single-center study was performed at a tertiary care center in India between August 2017 and September 2020 involving AMI patients. We performed echocardiography for all patients. Parameters such as left ventricle (LV) and atrium size, LV end-diastolic pressure, inferior vena cava (IVC) size and size variation, velocity stroke volume, and velocity time integral variation were measured. B-lines were recorded by scanning 32 regions on the anterior chest in the supine position using cardiac probes of echocardiography. Results A total of 184 patients were enrolled in the study with male predominance (82.1%). The mean age of patients was 58.2 ± 10.7 years. Dilated (>2.1 cm) and collapsible (<50%) IVC, and B-lines were significantly associated with heart failure (HF) (p<0.001; r=0.87 and p<0.001; r=0.74, respectively). The area under receiver operating characteristics (AUROC) curve to diagnose HF at a cut-off value of >10 for B-lines was 0.897 (0.842-0.951). AUROC curve for IVC size in diagnosing hypovolemia was 0.063 (0.000-0.130). Conclusions Volume status based on IVC size and B-lines detected by echocardiography has a strong prognostic value in AMI patients and should be included in the routine assessment of these patients.

Comparison of iso-effective and cost-effective high-dose-rate brachytherapy treatment schedules in cervical cancer - regional cancer center experience.

PURPOSE: The study is to evaluate the difference between outcomes of two high-dose-rate fractionation schedules in the treatment of intracavitary brachytherapy (ICBT) of cervical cancer. MATERIAL AND METHODS: A retrospective analysis of 163 cervical cancer patients was completed. All patients received external beam radiotherapy (EBRT) to whole pelvis with concurrent weekly chemotherapy, followed by ICBT with either 7 Gy per fraction in three fractions (arm A) or 9 Gy per fraction in two fractions (arm B). Median follow-up was 19 months. The outcomes were compared in terms of 2-year actuarial local control, disease-free survival, overall survival, and late toxicity in the two treatment arms. RESULTS: The 2-year actuarial local control rates in arm A and arm B were 88.5% and 91.5%, respectively. The actuarial 2-year disease-free survival rates in arm A and arm B were 85.9% and 82.6%, respectively. The actuarial 2-year overall survival in arm A and arm B were 95.7% and 100%, respectively (p = 0.06). There were 12.7% and 15.2% local failures in arm A and arm B, respectively. Distant metastases were seen in 8.5% and 7.6% in arm A and arm B, respectively. The 2-year actuarial risk of developing late rectal toxicity in arm A and arm B were 5.6% and 5.4%, respectively. The 2-year actuarial risk of developing late bladder toxicity in arm A and arm B were 2.8% and 2.2%, respectively. CONCLUSIONS: ICBT treatment with 9 Gy in two fractions offers equivocal local control rates and survival rates in cancer cervix cases with many advantages of short overall treatment time, improved patient compliance, cost effectiveness, and reduced exposure to aesthetic agents. The toxicities observed were few, low grade, and easily manageable.

Four percent formalin application for the management of radiation proctitis in carcinoma cervix patients: An effective, safe, and economical practice.

CONTEXT: Radiotherapy is a very effective treatment modality for pelvic malignancies such as carcinoma of the cervix. However, it is quite common for chronic radiation proctitis (CRP) to manifest after radical radiotherapy. CRP is a source of significant morbidity, and there is a lack of effective treatment modalities. There also exists a general lack of guidelines on management of CRP. AIMS: To assess the benefit from 4% formalin application for the treatment of Grade >2 CRP among patients previously treated with radical radiotherapy for cervical carcinoma. SETTINGS AND DESIGN: This retrospective descriptive study involved 29 eligible patients who were treated from November 2010 - November 2015 for CRP with 4% formalin application. MATERIALS AND METHODS: Of the 1864 patients of carcinoma cervix treated during the said patients, 29 patients fulfilled the eligibility criteria. Eligible patients were invited telephonically for follow-up and were assessed for response and complications of the procedure. RESULTS: The treatment of hemorrhagic radiation proctitis with local formalin instillation is effective, well tolerated and safe procedure. The procedure is inexpensive, technically simple and can be done on an outpatient basis. 62% patients had complete freedom from rectal bleed, while 34.5% patients had partial benefit. Only one patient required diversion colostomy for persistent bleeding.

The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology (FRACTION) program: innovative, high-throughput clinical screening of immunotherapies.

BACKGROUND: The unprecedented success of immuno-oncology (I-O) agents targeting the cytotoxic T lymphocyte-associated antigen 4 and programmed death-1/programmed death-ligand 1 pathways has stimulated the rapid development of other I-O agents against novel immune targets. Bristol-Myers Squibb has designed a novel phase II platform trial, the Fast Real-time Assessment of Combination Therapies in Immuno-ONcology (FRACTION) Program, to efficiently identify promising combinations for patients with specific malignancies. The concept and study design of the FRACTION Program-currently ongoing in patients with advanced non-small-cell lung cancer (FRACTION-Lung), gastric cancer (FRACTION-Gastric Cancer) and renal cell carcinoma (FRACTION-RCC)-are described. METHODS: The FRACTION Program comprises open-label, phase II studies that use adaptive randomisation designs with rolling combination regimens. Master Protocols provide the overall study design framework, whereas Sub-Protocols introduced over time provide details on specific I-O combination therapies to which patients may be randomised. In a Master Protocol, patients are enrolled into different Study Tracks based on characteristics such as prior I-O therapy experience. Patients who progress may be rerandomised to other combination regimens from any ongoing Sub-Protocol. Primary objectives are to assess objective response rate, median duration of response and progression-free survival rate at 24 weeks; the secondary objective is to investigate safety and tolerability. Biomarker collection before and on treatment will facilitate identification of patient subsets who benefit most from each therapy. CONCLUSIONS: The FRACTION Program allows for the evaluation of multiple I-O combinations through individual studies for specific tumours using an adaptive trial design and continuous enrolment.

An Integrated Assessment of the Effects of Immunogenicity on the Pharmacokinetics, Safety, and Efficacy of Elotuzumab.

Elotuzumab is a humanized, immunostimulatory anti-signaling lymphocytic activation molecule F7 (SLAMF7) IgG1 monoclonal antibody indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma (MM) who have received 1-3 prior therapies. We assessed the immunogenicity of elotuzumab as a monotherapy and in combination with bortezomib/dexamethasone and lenalidomide/dexamethasone in patients with MM in five clinical studies, including the pivotal ELOQUENT-2 trial (NCT01239797). Anti-drug antibody (ADA) prevalence was determined using a validated bridging assay. The prevalence of neutralizing antibodies (NAbs) was assessed in ADA-positive samples from ELOQUENT-2. Data from four trials of elotuzumab combined with lenalidomide/dexamethasone or bortezomib/dexamethasone (n = 390 evaluable patients) demonstrated that nine (2.3%) patients were ADA positive in baseline assays, 72 (18.5%) were ADA positive on-treatment or during follow-up, and two (0.5%) developed persistent ADAs. Patients treated with elotuzumab monotherapy had a higher incidence of elotuzumab ADAs than those on the combination therapy. In general, ADAs developed early and resolved after 2-4 months. Of 45 on-treatment ADA-positive patients in ELOQUENT-2, 19 had NAbs. Population pharmacokinetic modeling demonstrated an apparent increase in target-mediated elimination (higher V max, lower K M) in ADA-positive versus ADA-negative patients. ADAs were associated with lower elotuzumab steady-state exposure; however, this result may have been confounded by differential myeloma protein levels. ADAs/NAbs were not associated with hypersensitivity, infusion reactions, or loss of elotuzumab efficacy. Using a novel visualization, we also demonstrate that there is no clear relationship between the occurrence and titer values of ADA/NAbs and progression-free survival and best overall response status in patients treated with elotuzumab.

A review of stroke and pregnancy: incidence, management and prevention.

Stroke, defined as a focal or global disturbance of cerebral function lasting over 24h resulting from disruption of its blood supply, is a devastating event for a pregnant woman. This can result in long-term disability or death, and impact on her family and unborn child. In addition to pre-existing patient risk factors, the hypercoagulable state and pre-eclampsia need to be taken into account. The patterns and types of stroke affect pregnant women differ from the non-pregnant female population of child-bearing age. Like other thrombo-embolic diseases in pregnancy, stroke is essentially a disease of the puerperium. Population studies have estimated the risk of stroke at between 21.2 and 46.2 per 100,000. The US Nationwide Inpatient Sample, identified 2850 pregnancies complicated by stroke in the United States in 2000-2001, for a rate of 34.2 per 100,000 deliveries. There were 117 deaths, a mortality rate of 1.4 per 100,000. Both the mortality and disability rates were higher than previously reported, with 10-13% of women dying. With the increasing prevalence of obesity, hypertension and cardiac disease amongst women of child-bearing age, so is the incidence of stroke during pregnancy and the puerperium. In the United States, an alarming trend toward higher numbers of stroke hospitalizations during the last decade was demonstrated in studies from 1995 to 1996 and 2006 to 2007. The rate of all types of stroke increased by 47% among antenatal hospitalizations, and by 83% among post-partum hospitalizations. Hypertensive disorders, obesity and heart disease complicated 32% of antenatal admissions and 53% of post-partum admissions. In addition to pre-existing patient risk factors, the hypercoagulable state and pre-eclampsia need to be taken into account. The patterns and types of stroke affect pregnant women differ from the non-pregnant female population of child-bearing age. Like other thrombo-embolic diseases in pregnancy, stroke is essentially a disease of the puerperium.

Atom-based 3D-QSAR, molecular docking and molecular dynamics simulation assessment of inhibitors for thyroid hormone receptor α and ß.

The three-dimensional quantitative structure-activity relationship (3D-QSAR) for inhibitors of thyroid hormone receptors (TR) α and (TR) ß was studied. The training set of the TRα model generated a correlation coefficient (R(2)) = 0.9535, with standard deviation (SD) = 0.3016. From the test set of the TRα model, a Q(2) value for the predicted activities (= 0.4303), squared correlation (random selection R(2)-CV = 0.6929), Pearson-R (= 0.7294) and root mean square error (RMSE = 0.6342) were calculated. The P-value for TRα (= 1.411e-96) and TRß (= 2.108e-165) models indicate a high degree of self-reliance. For the TRß model, the training set yielded R(2) = 0.9424 with SD = 0.3719. From the test set of TRß, Q(2) value (= 0.5336), the squared correlation (R(2)-CV = 0.7201), the Pearson-R (= 0.7852) and RMSE for test set predictions (= 0.8630) all strengthen the good predictive competence of the QSAR model derived. Examination of internal as well as external validation supports the rationality and good predictive ability of the best model. Molecular docking explained the conformations of molecules and important amino acid residues at the docking pocket, and a molecular dynamics simulation study further uncovered the binding process and validated the rationality of docking results. The findings not only lead to a better understanding of interactions between these antagonists and thyroid hormone receptors α and ß, but also provide valuable information about the impact of structure on activity that will be very beneficial in the design of novel antagonists with preferred activity.

Utility of population pharmacokinetic modeling in the assessment of therapeutic protein-drug interactions.

Assessment of pharmacokinetic (PK) based drug-drug interactions (DDI) is essential for ensuring patient safety and drug efficacy. With the substantial increase in therapeutic proteins (TP) entering the market and drug development, evaluation of TP-drug interaction (TPDI) has become increasingly important. Unlike for small molecule (e.g., chemical-based) drugs, conducting TPDI studies often presents logistical challenges, while the population PK (PPK) modeling may be a viable approach dealing with the issues. A working group was formed with members from the pharmaceutical industry and the FDA to assess the utility of PPK-based TPDI assessment including study designs, data analysis methods, and implementation strategy. This paper summarizes key issues for consideration as well as a proposed strategy with focuses on (1) PPK approach for exploratory assessment; (2) PPK approach for confirmatory assessment; (3) importance of data quality; (4) implementation strategy; and (5) potential regulatory implications. Advantages and limitations of the approach are also discussed.

Quality-by-design: are we there yet?

In 2012, the Quality-by-Design and Product Performance Focus Group of AAPS conducted a survey to assess the state of adoption and perception of Quality-by-Design (QbD). Responses from 149 anonymous individuals from industry-including consultants-(88%), academia (7%), and regulatory body (4%), were collected. A majority of respondents (54% to 76%) reported high frequency of utilization of several tools and most QbD elements outlined by International Conference on Harmonization Q8, with design of experiments, risk assessment, and the quality target product profile ranked as the top three. Over two thirds of respondents agreed that the benefits of QbD included both the positive impact it can have on the patient (78%), as well as on internal processes such as knowledge management (85%), decision making (79%), and lean manufacture (71%). However, more than 50% from industry were neutral about or disagreed with QbD leading to a better return on investment. This suggests that, despite the recognized scientific, manufacture, and patient-related benefits, there is not yet a clearly articulated business case for QbD available. There was a difference of opinion between industry and regulatory agency respondents as to whether a QbD-based submission resulted in increased efficiency of review. These contrasting views reinforce the idea that QbD implementation can benefit from further dialog between industry and regulatory authorities. A majority of respondents from academia indicated that QbD has influenced their research. In total, the results indicate the broad adoption of QbD but also suggest we are yet in a journey and that the process of gathering all experience and metrics required for connecting and demonstrating QbD benefits to all stakeholders is still in progress.