Cell-cycle inhibition and immune microenvironment in breast cancer treated with ribociclib and letrozole or chemotherapy.

In this study, we performed genomic analyses of cell cycle and tumor microenvironment changes during and after ribociclib and letrozole or chemotherapy in the CORALLEEN trial. 106 women with untreated PAM50-defined Luminal B early breast cancers were randomly assigned to receive neoadjuvant ribociclib and letrozole or standard-of-care chemotherapy. Ki67 immunohistochemistry, tumor-infiltrating lymphocytes quantification, and RNA sequencing were obtained from tissue biopsies pre-treatment, on day 14 of treatment, and tumor specimens from surgical resection. Results showed that at surgery, Ki67 and the PAM50 proliferation scores were lower after ribociclib compared to chemotherapy. However, consistent reactivation of tumor cell proliferation from day 14 to surgery was only observed in the ribociclib arm. In tumors with complete cell cycle arrest (CCCA) at surgery, PAM50 proliferation scores were lower in the ribociclib arm compared to chemotherapy (p < 0.001), whereas the opposite was observed with tumor cellularity (p = 0.002). Gene expression signatures (GES) associated with antigen-presenting cells (APCs) and innate immune system activity showed increased expression post-chemotherapy but decreased expression post-ribociclib. Interferon-associated GES had decreased expression with CCCA and increased expression with non-CCCA. Our findings suggest that while both treatment strategies decreased proliferation, the depth and the patterns over time differed by treatment arm. Immunologically, ribociclib was associated with downregulated GES associated with APCs and the innate immune system in Luminal B tumors, contrary to existing preclinical data. Further studies are needed to understand the effect of CDK4/6 inhibition on the tumor cells and microenvironment, an effect which may vary according to tumor subtypes.

Environmental assessment, microstructural behaviour, stress-strain characteristics, and effect of exposure to extreme temperature on sustainable concrete made with dolomite mining residues.

Mining and extraction of stones and minerals play a significant role in many countries economic growth in the world. The production of dolomite minerals in various industries in India and other countries produces vast amounts of waste in different fractions. Disposal of these types of industrial wastes in an immense quantity causes environmental pollution. The performance of dolomite mining residues on concrete properties as a fine aggregate substitute was examined. The microstructural analysis was conducted on the concrete samples to find the effect of dolomite mining residues in concrete. The stress-strain behaviour of the dolomite mining residues concrete was studied. The effect of exposure to elevated temperature and freeze-thaw on concrete properties containing dolomite mining residues was found up to 100% at 10% incremental order. The thermogravimetric analysis (TGA) and differential thermogravimetry (DTG) tests were conducted on the dolomite mining residues and concrete samples. As a test result, concrete properties influence with the incorporation of the dolomite mining residues as a substitution of river sand, but no significant effect is observed in the concrete properties containing 10% dolomite mining residues. Up to 10% of dolomite production waste can be used as a sand substitute in concrete and other applications for sustainable development.

Effect of mechanically treated and untreated zinc tailing waste as cement substitute in concrete production: an experimental and statistical analysis.

Zinc tailing waste is a type of mine waste generated during the extraction of zinc metal. Disposal of a huge amount of mine tailing waste is an open area and tailing dam causing a negative impact on the natural ecosystem and human health. In this research study, the mechanical properties and durability performance of concrete containing zinc mine tailing waste was investigated through an experimental and statistical analysis. The mechanically treated and untreated zinc tailing waste was used as a cement substitute in concrete production. Concrete specimens were fabricated by replacing cement (0%, 5%, 10%, 15%, and 20%) with the mechanically treated and untreated zinc mine tailing waste. The effect of the zinc mine tailing waste was investigated by conducting the various mechanical (compressive strength and elastic modulus) tests, durability (ultrasonic pulse velocity, water absorption, chloride penetration, carbonation, sulfate attack) tests. The X-ray diffraction (XRD) analysis and scanning electron microscopy (SEM) on concrete samples were also conducted for microstructure analysis. According to the various tests conducted, all concrete properties showed comparable results at the 5% cement substitution in concrete by mechanically treated zinc tailing waste. However, the zinc tailing waste concrete was shown to be more sulphate resistance than the control concrete. Test findings suggest that it is feasible to use 10% mechanically treated and 5% untreated zinc tailing waste as a substitute for cement in concrete to reduce the adverse effect on the environment.

Retrospective review of the patient cases at a major trauma center in Nairobi, Kenya and implications for emergency care development.

INTRODUCTION: Low- and middle-income countries (LMICs) are continuing to experience a "triple burden" of disease - traumatic injury, non-communicable diseases (NCDs), and communicable disease with maternal and neonatal conditions (CD&Ms). The epidemiology of this triad is not well characterised and poses significant challenges to resource allocations, administration, and education of emergency care providers. The data collected in this study provide a comprehensive description of the emergency centre at Kenya's largest public tertiary care hospital. METHODS: This study is a retrospective chart review conducted at Kenyatta National Hospital of all patient encounters over a four-month period. Data were collected from financial and emergency centre triage records along with admission and mortality logbooks. Chief complaints and discharge diagnoses collected by specially trained research assistants were manually converted to standardised diagnoses using International Classification of Disease 10 (ICD-10) codes. ICD-10 codes were categorised into groups based on the ICD-10 classification system for presentation. RESULTS: A total of 23,941 patients presented to the emergency centre during the study period for an estimated annual census of 71,823. The majority of patients were aged 18-64 years (58%) with 50% of patients being male and only 3% of unknown sex. The majority of patients (61%) were treated in the emergency centre, observed, and discharged home. Admission was the next most common disposition (33%) followed by death (6%). Head injury was the overall most common diagnosis (11%) associated with admission. CONCLUSIONS: Trends toward NCDs and traumatic diseases have been described by this study and merit further investigation in both the urban and rural setting. Specifically, the significance of head injury on healthcare cost, utilisation, and patient death and disability points to the growing need of additional resources at Kenyatta National Hospital for acute care. It further demonstrates the mounting impact of trauma in Kenya and throughout the developing world.

Retrospective review of the patient cases at a major trauma center in Nairobi, Kenya and implications for emergency care development

Introduction:Low- and middle-income countries (LMICs) are continuing to experience a "triple burden" of disease - traumatic injury, non-communicable diseases (NCDs), and communicable disease with maternal and neonatal conditions (CD&Ms). The epidemiology of this triad is not well characterised and poses significant challenges to resource allocations, administration, and education of emergency care providers. The data collected in this study provide a comprehensive description of the emergency centre at Kenya's largest public tertiary care hospital.Methods:This study is a retrospective chart review conducted at Kenyatta National Hospital of all patient encounters over a four-month period. Data were collected from financial and emergency centre triage records along with admission and mortality logbooks. Chief complaints and discharge diagnoses collected by specially trained research assistants were manually converted to standardised diagnoses using International Classification of Disease 10 (ICD-10) codes. ICD-10 codes were categorised into groups based on the ICD-10 classification system for presentation.Results:A total of 23,941 patients presented to the emergency centre during the study period for an estimated annual census of 71,823. The majority of patients were aged 18-64 years (58%) with 50% of patients being male and only 3% of unknown sex. The majority of patients (61%) were treated in the emergency centre, observed, and discharged home. Admission was the next most common disposition (33%) followed by death (6%). Head injury was the overall most common diagnosis (11%) associated with admission. Conclusions:Trends toward NCDs and traumatic diseases have been described by this study and merit further investigation in both the urban and rural setting. Specifically, the significance of head injury on healthcare cost, utilisation, and patient death and disability points to the growing need of additional resources at Kenyatta National Hospital for acute care. It further demonstrates the mounting impact of trauma in Kenya and throughout the developing world

Dentinogenic ghost cell tumor-a rare case report with review of literature.

Dentinogenic ghost cell tumors (DGCT) are very rare tumors considered as solid variants of calcifying epithelial odontogenic cysts (CEOC). They are locally invasive neoplasms and their main characteristic features are ameloblastoma like odontogenic epithelial proliferation, an aberrant keratinization in the form of ghost cells and dysplastic dentin. DGCT occur as two forms intraosseous (central) and extra osseous (peripheral), of which more aggressive intraosseous variety requires careful monitoring and aggressive local resection to prevent recurrence. This paper discusses a case of a 14-year-old male patient with a complaint of swelling in his right mandibular premolar molar region since 4 months and missing permanent right mandibular canine and first premolar was also observed. The lesion was diagnosed with radiological, cytological and histopathological investigations which revealed it to be rarest entity.

Etiologies and Predictors of 30-Day Readmission and In-Hospital Mortality During Primary and Readmission After Transcatheter Aortic Valve Implantation.

There are sparse data on the etiologies and predictors of readmission after transcatheter aortic valve implantation (TAVI). The study cohort was derived from the National Readmission Data 2013, a subset of the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality. TAVI was identified using appropriate International Classification of Diseases, Ninth Revision, Clinical Modification codes. The coprimary outcomes were 30-day readmissions and in-hospital mortality during primary admission and readmission. Hierarchical 2-level logistic models were used to evaluate study outcomes. Our analysis included 5,702 (weighted n = 12,703) TAVI procedures. About 1,215 patients were readmitted (weighted n = 2,757) within 30 days during the study year. Significant predictors of readmission included transapical access (OR, 95% CI, p value) (1.23, 1.10 to 1.38, <0.01), diabetes (1.18, 1.06 to 1.32, p 0.004), chronic lung disease (1.32, 1.18 to 1.47, <0.01), renal failure (1.43, 1.24 to 1.65, <0.01), patients discharged to facilities (1.28, 1.14 to 1.43, <0.01), and those who had lengthier hospital stays during primary admission (length of stay >10 days: 3.06, 2.22 to 4.22, <0.01). Female gender (1.39, 1.16 to 1.68, <0.01), blood transfusion (1.88, 1.55 to 2.29, <0.01), use of vasopressors (3.63, 2.50 to 5.28, <0.01), hemodynamic support (6.39, 5.20 to 7.85, <0.01) and percutaneous coronary intervention (1.89, 1.30 to 2.74, 0.01) during primary admission were significant predictors of in-hospital mortality. Age and transapical access were significant predictors of in-hospital mortality during readmission. In conclusion, heart failure, pneumonia, and bleeding complications are among important etiologies of readmission in patients after TAVI. Patients who underwent transapical TAVI and those with slower in-hospital recovery and co-morbidities such as chronic lung disease and renal failure are more likely to be readmitted to the hospital.

Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers.

Targeted therapies against basal-like breast tumors, which are typically 'triple-negative breast cancers (TNBCs)', remain an important unmet clinical need. Somatic TP53 mutations are the most common genetic event in basal-like breast tumors and TNBC. To identify additional drivers and possible drug targets of this subtype, a comparative study between human and murine tumors was performed by utilizing a murine Trp53-null mammary transplant tumor model. We show that two subsets of murine Trp53-null mammary transplant tumors resemble aspects of the human basal-like subtype. DNA-microarray, whole-genome and exome-based sequencing approaches were used to interrogate the secondary genetic aberrations of these tumors, which were then compared to human basal-like tumors to identify conserved somatic genetic features. DNA copy-number variation produced the largest number of conserved candidate personalized drug targets. These candidates were filtered using a DNA-RNA Pearson correlation cut-off and a requirement that the gene was deemed essential in at least 5% of human breast cancer cell lines from an RNA-mediated interference screen database. Five potential personalized drug target genes, which were spontaneously amplified loci in both murine and human basal-like tumors, were identified: Cul4a, Lamp1, Met, Pnpla6 and Tubgcp3 As a proof of concept, inhibition of Met using crizotinib caused Met-amplified murine tumors to initially undergo complete regression. This study identifies Met as a promising drug target in a subset of murine Trp53-null tumors, thus identifying a potential shared driver with a subset of human basal-like breast cancers. Our results also highlight the importance of comparative genomic studies for discovering personalized drug targets and for providing a preclinical model for further investigations of key tumor signaling pathways.

Use of Tethered Enzymes as a Platform Technology for Rapid Analyte Detection.

BACKGROUND: Rapid diagnosis for time-sensitive illnesses such as stroke, cardiac arrest, and septic shock is essential for successful treatment. Much attention has therefore focused on new strategies for rapid and objective diagnosis, such as Point-of-Care Tests (PoCT) for blood biomarkers. Here we use a biomimicry-based approach to demonstrate a new diagnostic platform, based on enzymes tethered to nanoparticles (NPs). As proof of principle, we use oriented immobilization of pyruvate kinase (PK) and luciferase (Luc) on silica NPs to achieve rapid and sensitive detection of neuron-specific enolase (NSE), a clinically relevant biomarker for multiple diseases ranging from acute brain injuries to lung cancer. We hypothesize that an approach capitalizing on the speed and catalytic nature of enzymatic reactions would enable fast and sensitive biomarker detection, suitable for PoCT devices. METHODS AND FINDINGS: We performed in-vitro, animal model, and human subject studies. First, the efficiency of coupled enzyme activities when tethered to NPs versus when in solution was tested, demonstrating a highly sensitive and rapid detection of physiological and pathological concentrations of NSE. Next, in rat stroke models the enzyme-based assay was able in minutes to show a statistically significant increase in NSE levels in samples taken 1 hour before and 0, 1, 3 and 6 hours after occlusion of the distal middle cerebral artery. Finally, using the tethered enzyme assay for detection of NSE in samples from 20 geriatric human patients, we show that our data match well (r = 0.815) with the current gold standard for biomarker detection, ELISA-with a major difference being that we achieve detection in 10 minutes as opposed to the several hours required for traditional ELISA. CONCLUSIONS: Oriented enzyme immobilization conferred more efficient coupled activity, and thus higher assay sensitivity, than non-tethered enzymes. Together, our findings provide proof of concept for using oriented immobilization of active enzymes on NPs as the basis for a highly rapid and sensitive biomarker detection platform. This addresses a key challenge in developing a PoCT platform for time sensitive and difficult to diagnose pathologies.

Transplant patient classification and tacrolimus assays: more evidence of the need for assay standardization.

BACKGROUND: A global tacrolimus proficiency study recently showed clinically significant variability between laboratories, the inability of a common calibrator to harmonize methods, and differences in patient classification depending on the test method. The authors evaluated (1) the effect of a change in methodology on patient classification based on tacrolimus blood concentration and (2) the ability of 2 methods to position the concentration in a given specimen within the correct range. METHODS: A total of 839 consecutive samples were analyzed at The Rogosin Institute and New York Presbyterian Hospital for routine tacrolimus monitoring over 30 days. Concordance analysis between the methods was performed covering dosage target ranges of 8-10, 6-8, 4-6 ng/mL currently used at our center. Six Sigma Metrics were applied to statistically evaluate the discordance rate. RESULTS: Deming regression comparing liquid chromatography-tandem mass spectrometry and immunoassay yielded y = 0.927x - 0.24; 95% confidence interval, 0.903-0.951; R = 0.875; n = 839. There were 310 pairs (37%) discordant by 1, 21 (2.5%) discordant by 2, and 4 (0.5%) discordant by 3 therapeutic ranges. Surprisingly, 40% of patient samples were discordant when therapeutic ranges were 2 ng/mL wide. This discordant rate is equivalent to 1.7 Sigma and falls far below the minimum acceptable threshold of 3 Sigma. CONCLUSIONS: Both methods are capable of measuring tacrolimus in the clinically relevant range between 1 and 10 ng/mL, yet 40% of the samples were discordant with an unacceptable Sigma level. Standardization of tacrolimus assays will mitigate this issue.

Pharmacogenomics and the future of toxicology testing.

Pharmacogenomics is a useful tool in clinical toxicology for characterizing many gene polymorphisms associated with different pharmacokinetics or pharmacodynamics of exogenously administered drugs. These genetic variants may determine ranges of variation in such fundamental aspects as drug-metabolizing enzymes, drug transporters, drug receptors, or targets of drug action. Toxicologically significant drugs for which the FDA has required the manufacturer to identify relevant pharmacogenomics markers on the label include carisoprodol, citalopram, codeine, and risperidone. For personalized medicine, combining pharmacogenomics testing with therapeutic drug monitoring may allow the identification of individuals who need lower or higher doses, or even a different drug.

An assay to monitor bivalirudin levels on cardiopulmonary bypass.

Anticoagulation therapy for cardiopulmonary bypass in patients with recently diagnosed heparin-induced thrombocytopenia can be particularly challenging. Although heparin is the standard of care, in these situations anticoagulation is achieved with alternative agents such as direct thrombin inhibitors. Therapeutic concentrations are difficult to assess with direct thrombin inhibitors, and their use is riddled with bleeding and thrombotic complications. We report the successful use of a specific chromogenic antifactor IIa assay in a patient with heparin-induced thrombocytopenia who received anticoagulation therapy with bivalirudin during cardiopulmonary bypass for coronary artery bypass graft surgery.

Atypical serum immunofixation patterns frequently emerge in immunomodulatory therapy and are associated with a high degree of response in multiple myeloma.

The M-protein is the major reference measure for response in multiple myeloma (MM) and its correct interpretation is key to clinical management. The emergence of oligoclonal banding is recognized as a benign finding in the postautologous stem cell transplantation setting (ASCT) for MM but its significance during non-myeloablative therapy is unknown. In a study of the immunomodulatory combination BiRD, (lenalidomide and dexamethasone with clarithromycin), we frequently detected the emergence of mono- and oligo-clonal immunoglobulins unrelated to the baseline diagnostic M-protein. The new M-proteins seen on serum immunofixation electrophoresis were clearly different in either heavy or light chain component(s) from the original M-spike protein and were termed atypical serum immunofixation patterns (ASIPs). Overall, 24/72 (33%) patients treated with BiRD developed ASIPs. Patients who developed ASIPs compared with patients treated with BiRD without ASIPs, had a significantly greater overall response (100% vs. 85%) and complete response rates (71% vs. 23%). ASIPs were not associated with new clonal plasma cells or other lymphoproliferative processes, and molecular remissions were documented. This is the first time this phenomenon has been seen with regularity in non-myeloablative therapy for MM. Analogous to the ASCT experience, ASIPs do not signal incipient disease progression, but rather herald robust response.

Long-term transfusion of polymerized bovine hemoglobin in a Jehovah's Witness following chemotherapy for myeloid leukemia: a case report.

A 52-year-old female Jehovah's Witness presented with relapsed secondary acute myeloid leukemia. Because of chemotherapy-induced anemia, she was infused with the bovine hemoglobin (Hb)-based oxygen carrier HBOC-201 (Biopure) as the sole means of transfusion support. HBOC-201 has only been used for management of acute hemorrhage, and its utility in providing longer term transfusion support is unknown. Over a period of 18 days, a total dose of 1230 g of HBOC-201 was delivered. Although the patient succumbed to the disease after 18 days of treatment, this case documents our experience with the highest dose and duration of HBOC-201 ever used. Although possible renal toxicity could not be definitively excluded, the homogeneous extraction of oxygen by the brain in the presence of and perhaps from HBOC-201 was demonstrated.