Emerging Strategies for the Prevention of Immune Toxicities Associated with T cell-Engaging Cancer Therapies.

SUMMARY: Immune-related toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common side effects of bispecific antibody and chimeric antigen receptor (CAR) T-cell therapies of hematologic malignancies. As anti-inflammatory therapy (the standard of care) is variably effective in mitigating these toxicities after onset, here we discuss emerging evidence for shifting the strategy from mitigation to prevention.

T cell redirecting bispecific antibodies for multiple myeloma: emerging therapeutic strategies in a changing treatment landscape.

In recent years, the treatment landscape of multiple myeloma has continued to evolve with the introduction of novel immunotherapies. This progress has translated to improved overall survival for patients, but an unmet need remains in the heavily pretreated and high-risk subsets of patients. Emerging immunotherapies in the form of CAR-T cell therapies have been approved for multiple myeloma. However, CAR-T cell therapy has logistical limitations and there is a need for immunotherapies that are readily available, safe, and effective in RRMM. Currently, pending approval, there are many "off the shelf" bispecific antibodies being developed that target BCMA, GPRC5D, FcRH5 and other cell surface proteins. Preliminary efficacy data has suggested that these bispecific antibody therapies have similar response rates (∼50-80%) in heavily pretreated patients. Similarly, to CAR-T cell therapy, cytokine release syndrome and immune effector cell associated neurotoxicity syndrome are adverse events of key interest and incidence range from ∼40 to 90% and 3 to 20%, respectively. In this review, we highlight the various bispecific immunotherapies under development in the treatment of multiple myeloma with a focus on the data from clinical phase I and II studies.

Ecosystem CO2 release driven by wind occurs in drylands at global scale.

Subterranean ventilation is a non-diffusive transport process that provokes the abrupt transfer of CO2 -rich air (previously stored) through water-free soil pores and cracks from the vadose zone to the atmosphere, under high-turbulence conditions. In dryland ecosystems, whose biological carbon exchanges are poorly characterized, it can strongly determine eddy-covariance CO2 fluxes that are used to validate remote sensing products and constrain models of gross primary productivity. Although subterranean ventilation episodes (VE) may occur in arid and semi-arid regions, which are unsung players in the global carbon cycle, little research has focused on the role of VE CO2 emissions in land-atmosphere CO2 exchange. This study shows clear empirical evidence of globally occurring VE. To identify VE, we used in situ quality-controlled eddy-covariance open data of carbon fluxes and ancillary variables from 145 sites in different open land covers (grassland, cropland, shrubland, savanna, and barren) across the globe. We selected the analyzed database from the FLUXNET2015, AmeriFlux, OzFlux, and AsiaFlux networks. To standardize the analysis, we designed an algorithm to detect CO2 emissions produced by VE at all sites considered in this study. Its main requirement is the presence of considerable and non-spurious correlation between the friction velocity (i.e., turbulence) and CO2 emissions. Of the sites analyzed, 34% exhibited the occurrence of VE. This vented CO2 emerged mainly from arid ecosystems (84%) and sites with hot and dry periods. Despite some limitations in data availability, this research demonstrates that VE-driven CO2 emissions occur globally. Future research should seek a better understanding of its drivers and the improvement of partitioning models, to reduce uncertainties in estimated biological CO2 exchanges and infer their contribution to the global net ecosystem carbon balance.

Real-world assessment of isocitrate dehydrogenase inhibitor-associated differentiation syndrome.

Ivosidenib and enasidenib are targeted agents that inhibit mutant isocitrate dehydrogenase (IDH) enzymes, restoring normal cellular differentiation in affected acute myeloid leukemia patients. Both agents carry a risk of differentiation syndrome (DS), a potentially life-threatening complication. In this multicenter, retrospective study we sought to determine the real-world incidence and characterize DS in patients with a myeloid malignancy treated with an IDH inhibitor. Of 49 total patients, 15 patients (31%) had a documented diagnosis of DS and 8 patients (16%) met the criteria of DS by Montesinos, et al. The most common signs and symptoms of DS were dyspnea/hypoxia (56%), unexplained fever (56%), bone pain/arthralgia (44%), edema/weight gain (39%), and pleural/pericardial effusions (33%). Our study reports a higher real-world incidence of DS in patients treated with IDH inhibitors for myeloid malignancies than previously reported.

Venetoclax for the treatment of elderly or chemotherapy-ineligible patients with acute myeloid leukemia: a step in the right direction or a game changer?

INTRODUCTION: Acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis and high rates of relapse, especially in elderly patients who are ineligible to receive intensive chemotherapy. Venetoclax, an oral BCL-2 inhibitor, is approved by the Food and Drug Administration in combination with hypomethylating agents or low-dose cytarabine in newly-diagnosed AML patients who are ineligible to receive intensive chemotherapy. Confirmatory phase III VIALE-A and VIALE-C trials showed a composite complete remission rate of 66.4% and 48%, respectively. Thus, further validating venetoclax as an attractive therapeutic option in the AML treatment landscape. AREAS COVERED: A review of venetoclax in AML, focusing on preclinical and clinical data, toxicity profile, and mechanisms of resistance; and its strengths and weaknesses in regards to its current and future role in AML treatment is discussed. To find relevant studies, authors searched PubMed/Medline and ClinicalTrials.gov. EXPERT OPINION: The introduction of venetoclax-based combination therapies has greatly expanded the therapeutic options for elderly and chemotherapy-ineligible AML patients. Additional studies with extended follow-up are necessary to address remaining open questions such as (I) durability of responses, (II) head-to-head comparisons with intensive chemotherapy in selected patients (e.g. TP53 mutations), and (III) novel triplet combinations using an HMA-venetoclax backbone.

High dose cyclophosphamide for cytoreduction in patients with acute myeloid leukemia with hyperleukocytosis or leukostasis.

Hyperleukocytosis may lead to multiple medical emergencies. Hydroxyurea, intensive chemotherapy, and leukapheresis are used for cytoreduction. However, there is little data regarding the best approach. Here, we report on the efficacy and safety of high dose cyclophosphamide (HDCy; 60 mg/kg). 27 patients with acute myeloid leukemia or blast phase chronic myeloid leukemia who presented with white blood cell count (WBC) of ≥50x109/L or symptoms of leukostasis were treated with HDCy. Primary endpoint was early mortality (death within seven days of admission). Median WBC was 107 × 109/L at time of HDCy; 74% had leukostasis symptoms at presentation. Eight (29.6%) patients died within seven days of admission. Sustained WBC reduction was achieved in 18/24 (75%) evaluable patients with median nadir of 0.25 × 109/L. Adverse effects attributed to HDCy included tumor lysis syndrome (n = 7; 25.9%), disseminated intravascular coagulopathy (n = 5; 18.5%), and hemorrhagic cystitis (n = 1; 3.7%). HDCy was effective for cytoreduction and adverse effects were acceptable.

24 Hours: A Case of Multiorgan Failure Associated With COVID-19.

Coronavirus has caused thousands of deaths due to several mechanisms of injury including acute kidney injury (AKI). Most of the patients have a fast progression of the disease leading to death in the second week of hospital admission, however, here we have a case of a 58-year-old female who died in less than 24 hours of admission due to severe metabolic acidosis, acute respiratory distress syndrome (ARDS) and renal failure.

Soil water content effects on net ecosystem CO2 exchange and actual evapotranspiration in a Mediterranean semiarid savanna of Central Chile.

Biosphere-atmosphere water and carbon fluxes depend on ecosystem structure, and their magnitudes and seasonal behavior are driven by environmental and biological factors. We studied the seasonal behavior of net ecosystem CO2 exchange (NEE), Gross Primary Productivity (GPP), Ecosystem Respiration (RE), and actual evapotranspiration (ETa) obtained by eddy covariance measurements during two years in a Mediterranean Acacia savanna ecosystem (Acacia caven) in Central Chile. The annual carbon balance was -53 g C m-2 in 2011 and -111 g C m-2 in 2012, showing that the ecosystem acts as a net sink of CO2, notwithstanding water limitations on photosynthesis observed in this particularly dry period. Total annual ETa was of 128 mm in 2011 and 139 mm in 2012. Both NEE and ETa exhibited strong seasonality with peak values recorded in the winter season (July to September), as a result of ecosystem phenology, soil water content and rainfall occurrence. Consequently, the maximum carbon assimilation rate occurred in wintertime. Results show that soil water content is a major driver of GPP and RE, defining their seasonal patterns and the annual carbon assimilation capacity of the ecosystem, and also modulating the effect that solar radiation and air temperature have on NEE components at shorter time scales.

Oleophobicity of Biomimetic Micropatterned Surface and Its Effect on the Adhesion of Frozen Oil.

The relationship between the oleophobicity of micropatterned surfaces and the reduction of oil adhesion at low temperatures was explored by using siloxane elastomer surfaces as a model system. Polydimethylsiloxane (PDMS) surfaces were fabricated with varying oleophobicity from oleophilic to superoleophobic by combing the blending of trichloro(1H,1H,2H,2H-perfluorooctyl)silane (FDTS) into PDMS with the construction of bioinspired micropillars. The oil contact angles of micropillars were >130°, with the largest contact angle measured to be 146°. The micropillared surface showed remarkable self-cleaning properties; the contact angle hysteresis was <15°. The transparent oil droplets on PDMS surfaces of varied oleophobicity were frozen into a white-colored solid at -25 °C with the aid of a cooling system. Adhesion forces of the frozen oil droplets were obtained from the knock-off tests, showing that the adhesion forces dropped with the increased oleophobicity. The largest adhesion force was observed on the oleophilic flat surface, while the lowest adhesion force was on the highest oleophobic micropillared surface. The relative effectiveness of chemical and physical modifications on adhesion strength reduction was studied in terms of FDTS and micropillars, respectively. The results showed that a reduction of adhesion strength by 4% was reached by blending FDTS into flat PDMS, while a much more pronounced reduction of frozen oil adhesion strength by 60% was achieved by blending FDTS into PDMS micropillars; these results suggested a possible synergic effect of the FDTS chemistry and micropillar on the reduction of adhesion strength of frozen oil droplets.

Renal LECT2 amyloidosis: a newly described disorder gaining greater recognition.

Amyloidosis results from the pathologic deposition of beta pleated sheet fibrils within various organs including the kidney. Most often, the deposition is composed of the well-known monoclonal immunoglobulin light chains (AL) or serum amyloid A protein (AA). Recently, a new type of amyloidogenic protein was discovered, leukocyte chemotactic factor 2 (LECT2). This type of amyloid tends to have an affinity to kidney and liver and is recognized as a distinct clinico-pathologic type of amyloidosis, presenting with varying degrees of impaired kidney function and proteinuria. Herein, a case of this uncommon novel amyloidosis is presented with a brief review of the literature.

Diabetic nephropathy for the primary care provider: new understandings on early detection and treatment.

BACKGROUND: Diabetic nephropathy is the leading cause of renal disease in the United States, occurring in 20%-40% of patients with diabetes. This condition is a distinct manifestation of diabetic renal disease seen in patients with type 1 and type 2 diabetes. Despite clear screening and management recommendations, diabetic nephropathy remains substantially underdiagnosed. METHODS: This review presents recent guidelines and recommendations from varied work groups to identify, monitor, and halt the progression of diabetic nephropathy. Our search of the recent literature focused on diagnostic criteria, the latest screening recommendations, novel screening methods, current research, new treatment recommendations, and goals for early intervention. RESULTS: Current recommendations for early detection and treatment of diabetic nephropathy include yearly albumin to creatinine ratio checks and more frequent tests if indicated based on glomerular filtration rate and albuminuria; optimizing glucose control with a target hemoglobin A1c goal of <7%; initiating angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) as the first line in disease management with dual therapy of ACE inhibitors and ARBs no longer recommended; managing blood pressure with a goal of <140/90 mmHg as the target for all patients with diabetes; and initiating statin therapy for patients <50 years old and with concomitant chronic kidney disease and diabetes and in all patients with chronic kidney disease >50 years of age regardless of the coexistence of diabetes. CONCLUSION: With early detection, proper screening, and management, the impact of diabetic nephropathy may be better mitigated to lessen its impact on society and healthcare.

The human footprint in the carbon cycle of temperate and boreal forests.

Temperate and boreal forests in the Northern Hemisphere cover an area of about 2 x 10(7) square kilometres and act as a substantial carbon sink (0.6-0.7 petagrams of carbon per year). Although forest expansion following agricultural abandonment is certainly responsible for an important fraction of this carbon sink activity, the additional effects on the carbon balance of established forests of increased atmospheric carbon dioxide, increasing temperatures, changes in management practices and nitrogen deposition are difficult to disentangle, despite an extensive network of measurement stations. The relevance of this measurement effort has also been questioned, because spot measurements fail to take into account the role of disturbances, either natural (fire, pests, windstorms) or anthropogenic (forest harvesting). Here we show that the temporal dynamics following stand-replacing disturbances do indeed account for a very large fraction of the overall variability in forest carbon sequestration. After the confounding effects of disturbance have been factored out, however, forest net carbon sequestration is found to be overwhelmingly driven by nitrogen deposition, largely the result of anthropogenic activities. The effect is always positive over the range of nitrogen deposition covered by currently available data sets, casting doubts on the risk of widespread ecosystem nitrogen saturation under natural conditions. The results demonstrate that mankind is ultimately controlling the carbon balance of temperate and boreal forests, either directly (through forest management) or indirectly (through nitrogen deposition).

Assessing forest soil CO(2) efflux: an in situ comparison of four techniques.

A dynamic, closed-chamber infrared gas analysis (IRGA) system (DC-1: CIRAS-1, PP-Systems, Hitchin, U.K.) was compared with three other systems for measuring soil CO(2) efflux: the soda lime technique (SL), the eddy correlation technique (EC), and another dynamic, closed-chamber IRGA system (DC-2: LI-6250, Li-Cor, Inc., Lincoln, NE). Among the four systems, the DC-1 systematically gave the highest flux rates. Relative to DC-1, SL, EC and DC-2 underestimated fluxes by 10, 36 and 46%, respectively. These large and systematic differences highlight uncertainties in comparing fluxes from different sites obtained with different techniques. Although the three chamber methods gave different results, the results were well correlated. The SL technique underestimated soil CO(2) fluxes compared with the DC-1 system, but both methods agreed well when the SL data were corrected for the underestimation at higher fluxes, indicating that inter-site comparisons are possible if techniques are properly crosscalibrated. The EC was the only system that was not well correlated with DC-1. Under low light conditions, EC values were similar to DC-1 estimates, but under high light conditions the EC system seriously underestimated soil fluxes. This was probably because of interference by the photosynthetic activity of a moss layer. Although below-canopy EC fluxes are not necessarily well suited for measuring soil CO(2) efflux in natural forest ecosystems, they provide valuable information about understory gas exchange when used in tandem with soil chambers.