Citations

High-throughput shotgun proteomics is the mainstay of protein identification in biological samples. Efficient proteomic analysis requires streamlined and accurate workflows for protein identification. Database searching has been the most basic and reliable workflow for identifying the peptides and proteins that are present in the sample. This method derives peptides from a list of protein sequences and matches them against the experimental MS2 spectra. The resulting peptide spectrum matches are scored to quantify their goodness of fit. Spectral library searching has been recently developed as a fast, and viable, alternative to sequence database searching. This method attempts to identify the peptides by matching their corresponding experimental MS2 spectra to a library of curated MS2 peptide spectra. Each method has its own merit and application in the proteomics field. This chapter aims to highlight the foundations of peptide spectrum matching via protein sequence database and spectral library searching.

Recent meta-analyses and publications over the past 15 years have provided evidence showing there are considerable gender differences in the pharmacokinetics of metoprolol. Throughout this time, there have not been any research articles proposing a gender stratified dose-adjustment resulting in an equivalent total drug exposure. Metoprolol pharmacokinetic data was obtained from a previous publication. Data was modeled using nonlinear mixed effect modeling using the MONOLIX software package to quantify metoprolol concentration–time data. Gender-stratified dosing simulations were conducted to identify equivalent total drug exposure based on a 100 mg dose in adults. Based on the pharmacokinetic modeling and simulations, a 50 mg dose in adult women provides an approximately similar metoprolol drug exposure to a 100 mg dose in adult men.

Abstract Over the past few years, the management of multiple myeloma has changed. We have new guidelines regarding how to set the diagnosis, when to initiate therapy, and how to monitor treatment response. In 2014, the updated International Myeloma Working Group (IMWG) diagnostic criteria changed the definition of multiple myeloma from being a disease defined by symptoms to a disease defined by biomarkers. Today, modern combination therapies have reported up to 60% to 80% of patients reaching a complete response. As a logical and necessary step forward, investigators have explored strategies to detect minimal residual disease (MRD) and its correlation with clinical outcomes. Recent meta-analysis data show that MRD negativity is associated with longer progression-free survival and overall survival. In 2016, the updated IMWG response criteria include MRD as the deepest level of treatment response in multiple myeloma. Simultaneously, we are still quite behind in our understanding of the heterogeneous biology of multiple myeloma and its implications for therapy. Emerging DNA sequencing data show that newly diagnosed multiple myeloma patients have a broad range of mutations, which are distributed unevenly in multiple parallel subclones already present at diagnosis. To move beyond the ill-defined category of “high-risk multiple myeloma,” which confers to approximately 25% of all newly diagnosed patients, prospective studies are needed to dissect tumor biology and define multiple myeloma subtypes, and, based on biology, seek to define rational therapies for individual subtypes. This article discusses novel insights and gives perspectives on diagnosis and MRD monitoring and future directions for prognosis and clinical management of multiple myeloma. Clin Cancer Res; 22(22); 5428–33. ©2016 AACR. See all articles in this CCR Focus section, “Multiple Myeloma: Multiplying Therapies.”

ABSTRACT Staphylococcal prosthetic joint infections (PJIs) are associated with biofilm formation, making them difficult to treat; if managed with debridement and implant retention, rifampin-based therapy is usually employed. Rifampin resistance potentially challenges PJI treatment. In investigating the effects of rifampin monotherapy on methicillin-resistant Staphylococcus aureus (MRSA) foreign-body osteomyelitis in rats, we previously demonstrated that rifampin resistance was selected but that it disappeared 14 days following rifampin monotherapy (1) and that rifampin resistance occurred less frequently following two rounds than following one round of rifampin monotherapy (2). Here, we compared rifampin monotherapy followed by rifampin-vancomycin combination therapy to rifampin-vancomycin combination therapy alone in experimental MRSA foreign-body osteomyelitis. Animals treated with rifampin monotherapy followed by rifampin-vancomycin combination therapy had decreased quantities of bacteria 14 days following treatment completion ( P = 0.034) compared to those in animals treated with combination therapy alone. Additionally, some isolates recovered from animals treated with combination therapy alone, although still susceptible to rifampin, had higher MIC, minimum biofilm-inhibitory concentration (MBIC), and minimum biofilm-bactericidal concentration (MBBC) values than those of the inoculating strain. This suggests that rifampin may remain a feasible treatment option in foreign-body-associated orthopedic infections following the selection of rifampin resistance.

ABSTRACT We developed a rat model of methicillin-resistant Staphylococcus epidermidis (MRSE) foreign body-associated osteomyelitis and used it to compare tedizolid alone and in combination with rifampin against rifampin alone, vancomycin plus rifampin, and vancomycin alone. A clinical strain of MRSE was inoculated into the proximal tibia, and a stainless steel wire with a precolonized MRSE biofilm was implanted. Following a 1-week infection period, 92 rats received either no treatment ( n = 17) or 14 days of intraperitoneal tedizolid ( n = 15), tedizolid plus rifampin ( n = 15), rifampin ( n = 15), vancomycin plus rifampin ( n = 15), or vancomycin ( n = 15). Quantitative bone and wire cultures were performed after treatment completion and also 1 week after infection in a separate group of five rats. The median quantity of staphylococci in bone after the 1-week infection period was 4.89 log 10 CFU/g bone (interquartile range, 3.83 to 5.33 log 10 CFU/g bone); staphylococci were recovered from all associated wires. A median quantity of staphylococci of 3.70 log 10 CFU/g bone was detected in bones of untreated control rats after 3 weeks. Quantities of staphylococci in bones of all treatment groups except the group receiving vancomycin alone (2.78 log 10 CFU/g) were significantly lower than those for untreated controls, with no staphylococci being detected in the groups receiving rifampin monotherapy, tedizolid-plus-rifampin combination therapy, and vancomycin-plus-rifampin combination therapy. Quantities of staphylococci on wires from all treatment groups that included rifampin were significantly lower than those for untreated controls. No resistance to rifampin, tedizolid, or vancomycin was detected. Tedizolid combined with rifampin was active in a rat model of MRSE foreign body-associated osteomyelitis.

Abstract Treatment paradigms have changed rapidly for multiple myeloma, and immune therapies have taken center stage. Advances in therapies for myeloma have led to a dramatic improvement in the survival of patients with this incurable malignancy. The immune system is significantly impaired in patients with myeloma as a result of the disease leading to suppression of normal plasma cells as well the negative effects on cellular immunity. Given this scenario, immune approaches have not been successful until recently. Monoclonal antibodies directed against CD38 (daratumumab) and SLAMF7 (elotuzumab) are already in the clinic, and several other antibodies directed against different plasma cell antigens are under evaluation. Although immune checkpoint inhibition with PD-1 inhibitors had no clinical efficacy when the inhibitors were used as single agents, it has led to some dramatic results when the inhibitors are combined with immunomodulatory drugs such as lenalidomide and pomalidomide. Vaccination strategies have shown in vivo immune responses but no clear clinical efficacy. Newer approaches to vaccination with multiple antigens, used in combinations with immunomodulatory drugs and in the setting of minimal residual disease, have all increased possibility of this approach succeeding. Ex vivo effector cell expansion also appears to be promising and is in clinical trials. Finally, a chimeric antigen receptor T-cell approach appears to have some promise based on isolated reports of success and remains an area of intense investigation. Immune-based approaches can potentially augment or even supplant some of the current approaches and, given the low toxicity profile, may hold great potential in the early treatment of precursor-stage diseases. Clin Cancer Res; 22(22); 5453–60. ©2016 AACR. See all articles in this CCR Focus section, “Multiple Myeloma: Multiplying Therapies.”