Increased red blood cell (RBC) volume variation (RDW) has recently been shown to predict a wide range of mortality and morbidity: death due to cardiovascular disease, cancer, infection, renal disease, and more; complications in heart failure and coronary artery disease, advanced stage and worse prognosis in many cancers, poor outcomes in autoimmune disease, and many more. The mechanisms by which all of these diseases lead to increased RDW are unknown. Here we use a semi-mechanistic mathematical model of in vivo RBC population dynamics to dissect the factors controlling RDW and show that elevated RDW results largely from a slight reduction in the in vivo rate of RBC turnover. RBCs become smaller as they age, and a slight reduction in the rate of RBC turnover allows smaller cells to continue circulating, expanding the low-volume tail of the RBC population’s volume distribution, and thereby increasing RDW. Our results show that mildly extended RBC lifespan is a previously unrecognized homeostatic adaptation common to a very wide range of pathologic states, likely compensating for subtle reductions in erythropoietic output. A mathematical model-based estimate of the clearance rate may provide a novel early-warning biomarker for a wide range of morbidity and mortality.

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The ability to resist mechanical forces is necessary for the survival and division of bacteria and has traditionally been probed using specialized, low-throughput techniques such as atomic force microscopy and optical tweezers. Here we demonstrate a microfluidic technique to profile the stiffness of individual bacteria and populations of bacteria. The approach is similar to micropipette aspiration used to characterize the biomechanical performance of eukaryotic cells. However, the small size and greater stiffness of bacteria relative to eukaryotic cells prevents the use of micropipettes. Here we present devices with sub-micron features capable of applying loads to bacteria in a controlled fashion. Inside the device, individual bacteria are flowed and trapped in tapered channels. Less stiff bacteria undergo greater deformation and therefore travel further into the tapered channel. Hence, the distance traversed by bacteria into a tapered channel is inversely related to cell stiffness. We demonstrate the ability of the device to characterize hundreds of bacteria at a time, measuring stiffness at 12 different applied loads at a time. The device is shown to differentiate between two bacterial species, E. coli (less stiff) and B. subtilis (more stiff), and detect differences between E. coli submitted to antibiotic treatment from untreated cells of the same species/strain. The microfluidic device is advantageous in that it requires only minimal sample preparation, no permanent cell immobilization, no staining/labeling and maintains cell viability. Our device adds detection of biomechanical phenotypes of bacteria to the list of other bacterial phenotypes currently detectable using microchip-based methods and suggests the feasibility of separating/selecting bacteria based on differences in cell stiffness.

Immunotherapy combinations are used to improve outcomes in metastatic cancer, but evidence-based knowledge of appropriate starting doses for novel combinations is lacking. Phase I-III adult combination clinical trials (≥ 1 drug was immunotherapy; anti-PD-1, PD-L1, or CTLA-4) were reviewed (PubMed Jan 1, 2010 to Sep 1, 2016; ASCO 2014-2016, ASH/ESMO 2014-2015 abstracts). The safe dose for each drug used in each combination was divided by the single-agent recommended dose to calculate dose percentage. Additive dose percentage was the sum of each dose percentage. Overall, 84 studies (N = 3,526 patients, 59 combinations) were analyzed. In 50% of studies, all drugs could be administered at full dose; 63%, in the presence of anti-PD-1/PD-L1 and 36% with anti-CTLA-4. The lowest safe starting dose for a doublet combination including a second immunotherapy was 50% of each drug; 60%, for a targeted agent. Most doublet/triplets combining anti-PD-1/PD-L1 with cytotoxics were tolerable at full doses. Response rates (median [interquartile range]) were higher for 3-drug than 2-drug combinations (53% [33-63%] (N = 23 studies) vs. 23% [14-39%]) (N = 60 studies) (p < 0.0001) with similar rates seen for targeted, cytotoxic, biologic, or additional immunotherapy combinations (p = 0.35). In conclusion, anti-PD-1/PD-L1 checkpoint inhibitors can be safely given with a variety of other immunotherapy and targeted agents, albeit at about half dose. Doublet and triplet combinations with cytotoxics could mostly be given at full doses. Anti-CTLA-4 agents compromised dosing more than anti-PD-1/PD-L1 agents. Response rates were significantly higher for 3- versus 2-drug combinations.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Irinotecan is widely used as a chemotherapeutic drug to treat CRC. However, the mechanisms of acquired resistance to irinotecan in CRC remain inconclusive. In the present study, we established a novel irinotecan-resistant human colon cell line to investigate the underlying mechanism(s) of irinotecan resistance, particularly the overexpression of ABC transporters. The irinotecan-resistant S1-IR20 cell line was established by exposing irinotecan to human S1 colon cancer cells. MTT cytotoxicity assay was carried out to determine the drug resistance profile of S1-IR20 cells. The drug-resistant cells showed about 47-fold resistance to irinotecan and cross-resistance to ABCG2 substrates in comparison with S1 cells. By Western blot analysis, S1-IR20 cells showed significant increase of ABCG2, but not ABCB1 or ABCC1 in protein expression level as compared to that of parental S1 cells. The immunofluorescence assay showed that the overexpressed ABCG2 transporter is localized on the cell membrane of S1-IR20 cells, suggesting an active efflux function of the ABCG2 transporter. This finding was further confirmed by reversal studies that inhibiting efflux function of ABCG2 was able to completely abolish drug resistance to irinotecan as well as other ABCG2 substrates in S1-IR20 cells. In conclusion, our work established an in vitro model of irinotecan resistance in CRC and suggested ABCG2 overexpression as one of the underlying mechanisms of acquired resistance to irinotecan. This novel resistant cell line may enable future studies to overcome drug resistance in vitro and improve CRC treatment in vivo.

Background: Functional and aesthetic nasal operations are some of the most common plastic surgery procedures performed in the United States. The purpose of the study was to evaluate the effects of septoplasty, septorhinoplasty, and rhinoplasty procedures on postoperative olfactory function and their relationship to nasal airflow and quality of life. Methods: A systematic review and meta-analysis was performed evaluating olfactory function following nasal surgery. Preoperative and postoperative values for olfaction, nasal airflow, and quality of life/nasal symptoms were analyzed. The effect size was calculated from each study and used for meta-analysis. As studies evaluated patients at different points in the postoperative period, the latest time point reported by each study was used in the meta-analysis. The 95 percent confidence interval of the effect size was calculated for each study. Study quality was assessed using the Jadad and Methodological Index for Nonrandomized Studies instruments. All included studies were Level of Evidence II. Results: There were 25 included studies. Following nasal surgery, patients experienced significant improvements in olfaction (p < 0.001), nasal airflow (p < 0.001), and quality of life/nasal symptoms (p < 0.001). Patients often experienced a transient decrease in olfaction immediately after surgery, followed by improvement postoperatively. Preoperative olfactory dysfunction rates were low and postoperative dysfunction was equally low. Olfaction improvement was directly correlated with improvement in nasal airflow and quality of life. Conclusions: Functional and aesthetic nasal operations appear to significantly improve olfaction, which is directly correlated with nasal airflow. Some studies report a transient worsening of these measures in the immediate postoperative period, which subsequently improved at later time points.

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Six double-stranded DNA Streptomyces bacteriophages, HotFries, Moozy, RavenPuff, Scap1, Rainydai, and SenditCS, were isolated using the phytopathogen Streptomyces scabiei as a host. These phages have been identified as Siphoviridae and members of cluster BI by genomic analysis.