ALBERT

Description: Lateral submesoscale processes and their influence on vertical stratification at shallow salinity fronts in the central Bay of Bengal during the winter monsoon are explored using high-resolution data from a cruise in November 2013. The observations are from a radiator survey centered at a salinity-controlled density front, embedded in a zone of moderate mesoscale strain (0.15 times the Coriolis parameter) and forced by winds with a downfront orientation. Below a thin mixed layer, often ≤10 m, the analysis shows several dynamical signatures indicative of submesoscale processes: (i) negative Ertel potential vorticity (PV); (ii) low-PV anomalies with O(1–10) km lateral extent, where the vorticity estimated on isopycnals and the isopycnal thickness are tightly coupled, varying in lockstep to yield low PV; (iii) flow conditions susceptible to forced symmetric instability (FSI) or bearing the imprint of earlier FSI events; (iv) negative lateral gradients in the absolute momentum field (inertial instability); and (v) strong contribution from differential sheared advection at O(1) km scales to the growth rate of the depth-averaged stratification. The findings here show one-dimensional vertical processes alone cannot explain the vertical stratification and its lateral variability over O(1–10) km scales at the radiator survey.

Description: Air–Sea Interactions in the Northern Indian Ocean (ASIRI) is an international research effort (2013–17) aimed at understanding and quantifying coupled atmosphere–ocean dynamics of the Bay of Bengal (BoB) with relevance to Indian Ocean monsoons. Working collaboratively, more than 20 research institutions are acquiring field observations coupled with operational and high-resolution models to address scientific issues that have stymied the monsoon predictability. ASIRI combines new and mature observational technologies to resolve submesoscale to regional-scale currents and hydrophysical fields. These data reveal BoB’s sharp frontal features, submesoscale variability, low-salinity lenses and filaments, and shallow mixed layers, with relatively weak turbulent mixing. Observed physical features include energetic high-frequency internal waves in the southern BoB, energetic mesoscale and submesoscale features including an intrathermocline eddy in the central BoB, and a high-resolution view of the exchange along the periphery of Sri Lanka, which includes the 100-km-wide East India Coastal Current (EICC) carrying low-salinity water out of the BoB and an adjacent, broad northward flow (∼300 km wide) that carries high-salinity water into BoB during the northeast monsoon. Atmospheric boundary layer (ABL) observations during the decaying phase of the Madden–Julian oscillation (MJO) permit the study of multiscale atmospheric processes associated with non-MJO phenomena and their impacts on the marine boundary layer. Underway analyses that integrate observations and numerical simulations shed light on how air–sea interactions control the ABL and upper-ocean processes.

Description: The scale-dependent variance of tracer properties in the ocean bears the imprint of the oceanic eddy field. Anomalies in spice (which combines anomalies in temperature T and salinity S on isopycnal surfaces) act as passive tracers beneath the surface mixed layer (ML). We present an analysis of spice distributions along isopycnals in the upper 200 m of the ocean, calculated with over 9000 vertical profiles of T and S measured along ~4800 km of ship tracks in the Bay of Bengal. The data are from three separate research cruises—in the winter monsoon season of 2013 and in the late and early summer monsoon seasons of 2015 and 2018. We present a spectral analysis of horizontal tracer variance statistics on scales ranging from the submesoscale (~1 km) to the mesoscale (~100 km). Isopycnal layers that are closer to the ML-base exhibit redder spectra of tracer variance at scales ≲10 km than is predicted by theories of quasigeostrophic turbulence or frontogenesis. Two plausible explanations are postulated. The first is that stirring by submesoscale motions and shear dispersion by near-inertial waves enhance effective horizontal mixing and deplete tracer variance at horizontal scales ≲10 km in this region. The second is that the spice anomalies are coherent with dynamical properties such as potential vorticity, and not interpretable as passively stirred.

Description: It has recently been shown that the Naka antigen, which is absent in 3% to 11% of Japanese blood donors, is expressed on platelet glycoprotein IV (GPIV; CD36) (Tomiyama et al, BLOOD, 75:684, 1990). In the present studies, flow cytometry was used to distinguish differences in the reactivity of Naka+ and Naka- platelets with both OKM5, a monoclonal antibody that recognizes an epitope on GPIV, and with polyclonal anti- GPIV antibody. OKM5 was also used to screen 871 platelet concentrates prepared from healthy US blood donors. Three of these showed markedly deficient binding of 125I-OKM5 or an incidence of 0.34%. Two of these donors were re-accessed and showed less than 1% binding of 125I-OKM5 as compared with 10,300 +/- 1,500 binding sites per platelet in controls (n = 4). Platelets from these two US donors were radiolabeled (125I, 3H) and compared with control platelets and with platelets from Japanese Naka+ and Naka- donors by crossed immunoelectrophoresis, protein blots, immunoprecipitation, and two-dimensional gel electrophoresis. GPIV could not be detected by any of these techniques in the Naka- platelets nor in the donors whose platelets showed deficient binding of OKM5. These results suggest that GPIV functions as an isoantigen rather than an alloantigen in immunizing Naka- platelet recipients. This is the first report of the absence of a major platelet membrane GP in healthy blood donors.

Description: Glycoprotein IV (GPIV; CD36 or GPIIIb) is a cell surface glycoprotein that has been proposed as mediating a number of physiologically important processes such as the adhesion of platelets to thrombospondin (TSP) and collagen, the cytoadherence of Plasmodium falciparum-infected erythrocytes, and the TSP-dependent interaction of monocytes with platelets and macrophages. Because platelets of the Naka-negative phenotype have recently been shown to lack detectable GPIV, their availability offered the opportunity to test directly these hypotheses regarding its adhesive functions. It has been found that Naka-negative platelets and monocytes do not support cytoadherence of P falciparum- infected erythrocytes. Naka-negative platelets are deficient in the initial stages of their adhesion to fibrillar collagen and this defect is most marked under Mg(2+)-free conditions. Finally, the ability of Naka-negative platelets to bind TSP before or after activation is unimpaired as compared with normal controls. These results do not support a role for GPIV as the TSP receptor.

Description: Introduction: Despite high initial success rates in the treatment of pediatric HL, nearly 20% of patients develop resistant / relapsed disease. While high-dose chemotherapy with autologous stem cell transplantation has improved outcomes, the best of these regimens still have limited success rates and also such therapies are not easily available for most patients in Low and Middle Income Countries (LMICs). Novel therapeutic agents are needed in this setting. Bendamustine is an alkylating agent with clinical activity against various adult lymphomas, including limited data supporting its use in heavily pretreated adult HL patients. There is no such data in pediatric HL patients. Here we retrospectively report the results of single agent bendamustine salvage regimen in pediatric patients with refractory/relapsed HL. Methods: Retrospective analysis of children with relapsed / refractory HL, who underwent treatment from January 2013 to February 2015, was performed. These patients, who were ineligible for autologous stem cell transplantation (ASCT) or had relapsed after ASCT (1), received bendamustine 120 mg/m2 as a 30 minutes infusion on days 1 and 2 every 28 days with growth factor support. Total 6 cycles were planned for each patient. Early response was evaluated using PET-CT following 2 cycles of bendamustine and best response was evaluated post completion of 6 cycles of bendamustine. Results: Of the 10 patients who were started on bendamustine, 8 received at least 2 cycles of bendamustine and were evaluable for response assessment. Of the 8, 7 were males and 1 female; median age was 13.5 years (range 5 to 15 years); the histology was mixed cellularity in 5 (62%) & nodular sclerosis in 3 (38%). Patients had received a median of 3 prior treatments (range 1 to 5). 5 had relapsed HL and 3 had primary progressive disease. On evaluation for early PET-CT response post 2 cycles of bendamustine, 4 patients (50%) had Complete Remission (CR) and 4 patients (50%) had Partial Remission (PR) with an Overall Response Rate (ORR) of 100%. One patient with PR post 2 cycles underwent haploidential allo-SCT and later died of sepsis. The remaining 7 patients went on to receive 6 cycles of bendamustine, 6 of them (85%) achieved CR and continue to be in CR. 1 patient who was in PR was started on lenalidomide plus celecoxib maintenance and died of sepsis at home post chicken pox infection at 7 months. The median follow-up for all 8 patients is 15 months (range 6 to 24 months). In general the treatment was well tolerated and toxicities, both hematological (grade II thrombocytopenia in 2 and febrile neutropenia in 1 patient) and extra-hematological were manageable. Conclusions: Within the limits of an observational retrospective study, these data indicates that bendamustine shows its efficacy in patients with relapsed/refractory HL, without any significant toxicity. It produces durable responses in patients with relapsed/refractory HL and may be an effective bridge to further therapeutic interventions. It may also be used earlier in the treatment strategy of HL and in combination with other active drugs. Disclosures Off Label Use: Bendamustine is used in treatment of relapsed/refractory Hodgkin Lymphoma, though it is not FDA approved for same at present..

Description: White blood cell counts (WBC) and absolute neutrophil counts (ANC) are well-established predictors of a patient's risk of fever and infections or febrile neutropenia (FN). Currently, patients at risk of FN due to cancer chemotherapy, idiosyncratic drug-reactions or congenital neutrophil disorders are monitored at hospital or clinic laboratories. For many patients, effective and frequent monitoring is difficult due to the time required and costs of repeated laboratory visits. We herein present the first results for a novel device called Athelas One, a miniature point-of-care hematology analyzer suitable for at home monitoring of WBC and ANC. Methods: Athelas One (A1) is a small cylindrical device with a built-in, single head, light microscope. To determine the WBC and ANC, a small drop of blood (~ 3.5 uL) from a finger stick or an anticoagulated blood sample is drawn by capillary action onto a specially designed microfluidic test strip which creates a stained, precisely dimensioned monolayer of blood cells. The slide is then inserted into the device which scans the test strip and reports the WBC and ANC based on an image analysis process (Computer Vision). We compared results for A1 with a standard laboratory counter [Sysmex XE5000 (SX)]. Results: Initially, A1's reproducibility was demonstrated using 43 blood samples with a wide range of known WBCs (i.e., samples with normal counts, leukocytosis, leukopenia, neutropenia, neutrophilia) run on 4 devices using a single lot of test strips. The A1 results were then compared to SX results using the Passing Bablok Regression with Bootstrap method. These results showed strong linearity and comparability between paired anti-coagulated venous blood samples and the blood samples compared to finger prick capillary blood samples collected almost simultaneously. The slope and intercept indicated a linear relationship, with a 95% confidence for interval slope and intercept containing 1 and 0 respectively. (Comparisons: A1 blood to SX blood: WBC, r=0.998, ANC, r=0.989; A1 capillary to SX blood: WBC, r=0.998, ANC, r=0.97). Table 1 and Figure 1 show a summary of the comparisons. In addition to these results, we have tested 18 samples with WBC 〈 1.0 x 109/L with closely comparable results for A1 and standard hospital counter. Summary: These initial results show that the WBC and ANC can be accurately determined with a finger stick drop of blood and this point-of-care hematology analyzer. Given its small size, ease of use and accuracy, the device is suitable for home monitoring. Disclosures Dale: Athelas, Inc.: Equity Ownership; Amgen: Consultancy, Research Funding; Sanofi-Aventi: Consultancy, Honoraria; Cellerant: Other: Scientific Advisory Board; Hospira: Consultancy; Prolong: Consultancy; Beheringer-Ingelheim: Consultancy; Coherus: Consultancy. Navarro-De La Vega:Athelas, Inc.: Employment. Parthasarathy:Athelas, Inc.: Employment, Equity Ownership. Bodapati:Athelas, Inc.: Employment, Equity Ownership, Patents & Royalties: patent owned by Athelas on the Athelas One device. Virey:Athelas, Inc.: Employment, Equity Ownership, Patents & Royalties: patent owned by Athelas on the Athelas One device. Moffatt:Athelas, Inc.: Employment, Equity Ownership, Patents & Royalties: patent owned by Athelas on the Athelas One device. Tandon:Athelas, Inc.: Employment, Equity Ownership, Patents & Royalties: patent owned by Athelas on the Athelas One device.

Description: Purpose Although minimal residual disease (MRD) is an established surrogate marker for outcomes following treatment with chemoimmunotherapy, less is known about the value of MRD in chemotherapy-free treatments in the first-line setting. We investigated the prognostic value of MRD detection after a fixed-duration treatment of venetoclax plus obinutuzumab (VenG) with respect to clinical and genetic risk factors and source of material in previously untreated patients (pts) with CLL and coexisting conditions. Methods In this multinational, open-label, Phase 3 trial, 432 previously untreated pts with a Cumulative Illness Rating Scale score 〉6 and/or an estimated creatinine clearance

Description: GPVI is a major platelet collagen signaling receptor associated with the ITAM-containing FcRγ in the platelet membrane. Autoantibodies to GPVI result in ADAM10-mediated cleavage and loss of receptor function. We now report a young woman with a history of autoimmune and kidney disease associated with systemic lupus erythematosus, and a strong circulating antibody to GPVI. The patient has been followed over a 3-year period. Particularly studied were (i) the platelet aggregation response to collagen (and convulxin (Cvx)), (ii) platelet GPVI levels (flow cytometry and Western blot (WB)), (iii) plasma soluble GPVI levels (GPVIs, dual antibody ELISA with capture and biotinylated detction MoAbs), and (iv) circulating anti-GPVI antibody titres (ELISA using recombinant GPVIs). When first studied in 2006, the patient had a normal platelet count but a virtual absence of platelet aggregation to collagen and Cvx. Nevertheless, her platelets responded to other agonists including cross-linking FcRγIIA by way of the monoclonal antibody, IV.3, showing that the PLCγ2-dependent signaling pathway shared with GPVI-FcRγ was retained. Western blotting with a series of MoAbs to GPVI (extracellular and intracellular domains) and other platelet receptors showed a major and specific deficit of GPVI with appearance of GPVI dimer and a 47 kDa degradation product. Other platelet receptors known to be sensitive to metalloprotease cleavage, GPIbα, P-selectin, TLT-1 were not reduced. However, FcRγ was moderately decreased in WB. Interestingly, the patient’s plasma was able to activate normal platelets, a phenomenon blocked by recombinant GPVI-Fc protein but not by IV.3 showing that it was independent of FcRγIIA and probably related to GPVI dimerization. Her plasma also specifically blocked the response of control platelets to Cvx in a time-dependent manner. Studies continued in 2007 when the patient additionally experienced neurological and vascular problems. Platelet expression of GPVI continued to be severely reduced by WB, and ELISA confirmed strong anti-GPVI plasma antibody titers. Plasma GPVIs levels were undetectable compared to control donors. Transfusion of donor platelets prior to a renal biopsy was unsuccessful; they were rapidly cleared and failed to correct the platelet defect. The patient was now subjected to increasingly strict immunosuppressive medication including corticoids (prednisolone), imurel (azathioprine) then endoxan (cyclophosphamide). A large reduction in plasma anti-GPVI levels, the appearance of GPVIs in the patient’s plasma (the ELISA results were confirmed by WB of plasma samples), the partial restoration of both platelet GPVI levels and the platelet collagen response accompanied these treatments which was paralleled by an improvement in her nephrotic syndrome. Our results suggest that this patient developed a potent anti-GPVI antibody responsible for the loss of platelet GPVI, with the possible clearance of GPVIs by immune complex formation. The activity of the antibody was much reduced by immunotherapy; further studies are required to know whether this is related to the improvement in her clinical state.