S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes.

Multiple myeloma is characterized by clonal proliferation of plasma cells that accumulate preferentially in the bone marrow (BM). The tumor microenvironment is one of the leading factors that promote tumor progression. Neutrophils and monocytes are a major part of the BM tumor microenvironment, but the mechanism of their contribution to multiple myeloma progression remains unclear. Here, we describe a novel mechanism by which S100A8/S100A9 proteins produced by BM neutrophils and monocytes promote the expansion of megakaryocytes supporting multiple myeloma progression. S100A8/S100A9 alone was not sufficient to drive megakaryopoiesis but markedly enhanced the effect of thrombopoietin, an effect that was mediated by Toll-like receptor 4 and activation of the STAT5 transcription factor. Targeting S100A9 with tasquinimod as a single agent and in combination with lenalidomide and with proteasome inhibitors has potent antimyeloma effect that is at least partly independent of the adaptive immune system. This newly identified axis of signaling involving myeloid cells and megakaryocytes may provide a new avenue for therapeutic targeting in multiple myeloma. Significance: We identified a novel mechanism by which myeloid cells promote myeloma progression independently of the adaptive immune system. Specifically, we discovered a novel role of S100A8/S100A9, the most abundant proteins produced by neutrophils and monocytes, in regulation of myeloma progression via promotion of the megakaryocyte expansion and angiogenesis. Tasquinimod, an inhibitor of S100A9, has potent antimyeloma effects as a single agent and in combination with lenalidomide and with proteasome inhibitors.

Perioperative group and save testing are not routinely indicated for emergency laparoscopic appendicectomy and laparoscopic hernia repairs: A North West London retrospective study.

INTRODUCTION: Two valid group and saves are commonly required for patients undergoing laparoscopic appendicectomy and laparoscopic hernia repairs preoperatively; however, perioperative blood transfusions are seldom required. This is financially burdensome and frequently leads to delays in theatre lists. We performed a retrospective analysis to investigate blood transfusions performed perioperatively and within 28 days of these procedures. METHOD: We used our electronic records to collect data of all laparoscopic appendectomies and laparoscopic hernia repairs between March 2017 and March 2021. Patients of any age undergoing these operations were included. Patients requiring concomitant intra-abdominal surgery or who had incomplete medical records were excluded. RESULTS: A total of 1891 patients were included, of which 1462 (77.3%) had a laparoscopic appendicectomy versus 429 (22.7%) who had a laparoscopic hernia repair. In all, 3507 group and saves were taken costing £47,398.50. One patient (0.068%) required emergency blood transfusion (4 units of red cells) secondary to major haemorrhage. CONCLUSION: Our findings demonstrate that the incidence of perioperative blood transfusions for laparoscopic appendicectomy and laparoscopic hernia repairs is low, challenging the indication for routine preoperative group and saves.

miR-196b-TLR7/8 Signaling Axis Regulates Innate Immune Signaling and Myeloid Maturation in DNMT3A-Mutant AML.

PURPOSE: DNMT3A mutations confer a poor prognosis in acute myeloid leukemia (AML), but the molecular mechanisms downstream of DNMT3A mutations in disease pathogenesis are not completely understood, limiting targeted therapeutic options. The role of miRNA in DNMT3A-mutant AML pathogenesis is understudied. EXPERIMENTAL DESIGN: DNA methylation and miRNA expression was evaluated in human AML patient samples and in Dnmt3a/Flt3-mutant AML mice. The treatment efficacy and molecular mechanisms of TLR7/8-directed therapies on DNMT3A-mutant AML were evaluated in vitro on human AML patient samples and in Dnmt3a/Flt3-mutant AML mice. RESULTS: miR-196b is hypomethylated and overexpressed in DNMT3A-mutant AML and is associated with poor patient outcome. miR-196b overexpression in DNMT3A-mutant AML is important to maintain an immature state and leukemic cell survival through repression of TLR signaling. The TLR7/8 agonist resiquimod induces dendritic cell-like differentiation with costimulatory molecule expression in DNMT3A-mutant AML cells and provides a survival benefit to Dnmt3a/Flt3-mutant AML mice. The small molecule bryostatin-1 augments resiquimod-mediated AML growth inhibition and differentiation. CONCLUSIONS: DNMT3A loss-of-function mutations cause miRNA locus-specific hypomethylation and overexpression important for mutant DNMT3A-mediated pathogenesis and clinical outcomes. Specifically, the overexpression of miR-196b in DNMT3A-mutant AML creates a novel therapeutic vulnerability by controlling sensitivity to TLR7/8-directed therapies.

Patient Experience on a Hospital Oncology Service Before and After Implementation of a No-Visitor Policy During COVID-19.

Hospital visitor restriction policies prompted by Coronavirus Disease 2019 (COVID-19) may lead to a less comfortable or informed inpatient experience for oncology patients admitted for non-COVID-19 conditions. We surveyed oncology inpatients before (n = 47) and after (n = 65) implementation of a no-visitor policy using a validated questionnaire to measure patient experience. Results revealed no significant difference in the percentage of patients reporting "no problems" (P < .05) in all questions. Patient experience was not adversely impacted by visitor restrictions enacted in response to COVID-19 on an oncology service, as measured by a questionnaire capturing common concerns among inpatients.

Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.

PURPOSE: Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need.Experimental Design: We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC in vitro and in vivo. RESULTS: ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib. CONCLUSIONS: These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC.

Chemical Characterization of Nanoparticles and Volatiles Present in Mainstream Hookah Smoke.

Waterpipe smoking is becoming more popular worldwide and there is a pressing need to better characterize the exposure of smokers to chemical compounds present in the mainstream smoke. We report real-time measurements of mainstream smoke for carbon monoxide, volatile organic compounds and nanoparticle size distribution and chemical composition using a custom dilution flow tube. A conventional tobacco mixture, a dark leaf unwashed tobacco and a nicotine-free herbal tobacco were studied. Results show that carbon monoxide is present in the mainstream smoke and originates primarily from the charcoal used to heat the tobacco. Online measurements of volatile organic compounds in mainstream smoke showed an overwhelming contribution from glycerol. Gas phase analysis also showed that very little filtration of the gas phase products is provided by the percolation of mainstream smoke through water. Waterpipe smoking generated high concentrations of 4-100 nm nanoparticles, which were mainly composed of sugar derivatives and especially abundant in the first 10 min of the smoking session. These measured emissions of volatiles and particles are compared with those from a reference cigarette (3R4F) and represent the equivalent of the emission of one or more entire cigarettes for a single puff of hookah smoke. Considerations related to the health impacts of waterpipe smoking are discussed.

Identifying risk and protective factors related to depressive symptoms among Northern Plains American Indian women cancer survivors.

Cancer is the leading cause of death among American Indian and Alaska Native (AIAN) women, and depressive symptoms have been linked to higher mortality, but research on depressive symptoms among AIAN cancer patients has been scant. The purpose of this exploratory study was, using the Framework of Historical Oppression, Resilience, and Transcendence, to examine risk and protective factors related to depressive symptoms in American Indian (AI) women cancer survivors. We examined the relationships of adverse childhood experiences (ACE), perceived health status, resilience, and social support with depressive symptoms in Northern Plains AI women cancer survivors. We used a cross-sectional design with purposive sampling of 73 female cancer survivors (aged 18 years or older) between June 2014 and February 2015. Hierarchical multiple regression was used to test three sets of variables in relation to depressive symptoms: (1) sociodemographics, (2) risk factors (ACE and perceived health), and (3) protective factors (psychological resilience and social support). Approximately 47 percent of participants had probable depressive symptoms. Depressive symptoms were inversely associated with perceived health, psychological resilience, and social support. These results support bolstering existing social support among AI cancer patients and survivors as well as prevention and intervention efforts that strengthen resilience.