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Highlights • The National Marrow Donor Program (NMDP) received preliminary search requests for over 3300 domestic and 3700 international allogeneic hematopoietic cell transplant candidates during the initial phase of the coronavirus disease 2019 (COVID-19) pandemic. • Despite a decrease in preliminary search requests, the number of unrelated donor grafts infused at domestic transplant centers following the initial phase of COVID-19 was only 4% less than the same period of time 1 year earlier. • Of over 2800 transportation legs and over 1600 transports completed through the NMDP, only 1 product was delivered outside of the requested time window in the initial period after COVID-19., The impact of the coronavirus disease 2019 (COVID-19) pandemic on hematopoietic cell transplant (HCT) donor registries and transplant center (TC) practices is underreported. This article reports on the National Marrow Donor Program (NMDP) Be The Match Registry and its coordinating the provision of unrelated donor (URD) products to domestic and international TCs during the initial 3 months of the COVID-19 pandemic (March through May 2020). Specifically, NMDP data are presented for disease indications for transplant, URD search volumes and availability, graft requests and processing, courier utilization and performance, and conversion rates from formal donor search and workup to graft collection and shipment. Data following the onset of COVID-19 are compared to the immediate 3 months prior to the COVID-19 pandemic (December 2019 through February 2020) and the same quarter 1 year prior to COVID-19 (March through May 2019). During the initial onset of COVID-19 and compared to 1 year prior, TCs requested and the NMDP performed less donor searches. More multiple URD and direct to workup requests were processed by the NMDP, which likely reflected reductions in donor availability. Yet TCs continued to perform allogeneic transplants for acute disease indications like acute leukemia and myelodysplasia, using more cryopreserved grafts than before COVID-19. In comparison to prepandemic patient cycle conversion rates and durations, the NMDP was able to convert patient cycles at nearly the same or higher rates and in similar or shorter periods of time. Last, despite significant challenges caused by the pandemic, including interruptions in domestic courier services and travel restrictions, graft products were delivered to and received by TCs in similar periods of time than before COVID-19. Taken together, these data show that NMDP service line operations continued to function effectively during the early phases of the COVID-19 pandemic, ensuring requests for and delivery of URD products to domestic and international allogeneic HCT recipients.

Litter and vegetation under forest canopy (i.e., understory vegetation) are known to reduce soil erosion and contribute substantially to evapotranspiration. However, previous studies rarely examined understory water interception. We conducted a comprehensive study of rainfall partitioning using a water balance equation that included both overstory and understory components in a Chinese fir (Cunninghamia lanceolata) plantation and a nearby naturally regenerated Castanopsis (C. carlesii) forest of similar age in southeastern China. Understory interception was measured by submerging understory components (vegetation and litter) in water for 24 h, which gave an estimate of the amount of water retained (i.e., water holding capacity). The total interception loss of rainfall events (>9.8 mm) that generated surface runoff converged between the two forests, a result of a smaller overstory interception loss (20%) coupled with a greater understory interception loss (14%) in the Chinese fir plantation relative to the Castanopsis forest (overstory 25% and understory 11%). The convergence of the total interception contributed to the convergence of the surface runoff, 1% of the rainfall in both forests. Furthermore, the throughfall partition (78%) was greater whereas the stemflow partition (2%) was smaller in the Chinese fir plantation relative to the Castanopsis forest (throufhfall 70% and stemflow 5%). These patterns in rainfall partitioning could be explained by the greater development of the understory vegetation (hence greater understory interception loss) in the Chinese fir plantation, lower canopy leaf area index (hence smaller overstory interception loss and greater throughfall), and rougher barks (hence smaller stemflow) of Chinese fir trees compared to that of Castanopsis trees. Our study illustrated that a comprehensive evaluation of interception loss must take into account understory components.

Quantifying ecosystem resilience is critical for predicting how shifts in disturbance regime affect ecosystem structure and function as a result of recent climate change. Studies of disturbance-ecosystem interactions often focus on one or a few disturbance events but the interactions may vary considerably among disturbance events. We used a 25-year LAI (leaf area index) record of the Fushan Experimental Forest (FEF) of northeastern Taiwan to explore forest LAI resilience to annual typhoon disturbance. The four typhoons of 1994 caused the most dramatic change of LAI in both the magnitude and the rate, as well as the longest time for a full recovery. However, typhoons varied in their effects, and not all intense typhoons caused major impact suggesting that result derived from one or a few disturbance events is unlikely to capture the full spectrum of disturbance effect. Using LAI of 4.26 measured following a non-typical year of no typhoon occurrence as a reference, it took 11─16 years before the predicted LAI to return to the reference level, which represents the resilience (time to return) of the forest LAI under minimal typhoon effects. Using the event-based analyses, the average degree of return was 0.86, with values as low as 0.45, suggesting that the LAI of the FEF is not always able to fully recover within the inter-typhoon time period (

Diisobutyl ketone (DIBK) and diisobutyl carbinol (DIBC) are important organic solvents widely used as industrial intermediates. It was hypothesized that DIBC and DIBK have common metabolic pathways and metabolites, and as such, toxicological data on DIBK could be used to characterize the hazards of DIBC. To confirm or refute this hypothesis a comparative metabolism and pharmacokinetics assessment of DIBK and DIBC was conducted. Dosing was via single oral gavage dosing in male SD rats, followed by blood collection, metabolite identification, major biomarker quantitation, and pharmacokinetics analysis. Overall, the major metabolites of both DIBC and DIBK in blood were their corresponding monohydroxylated metabolites (DIBC alcohol and DIBK alcohol) with the site of hydroxylation at the σ and σ-1 positions, respectively. Quantitative analysis of DIBC, DIBK, DIBC-alcohol, and DIBK-alcohol in blood samples collected from 5min to 120h after single dosing indicated the following: (1) DIBC and DIBK are both well absorbed following oral gavage with substantial evidence of enterohepatic recirculation of DIBK, DIBC, DIBK-alcohol, and DIBC-alcohol; (2) DIBK and DIBC are interconverted metabolically in rats; (3) DIBC and DIBK have similar bioavailability after oral administration; (4) higher systemic exposure was found for DIBK-alcohol than DIBC-alcohol, implying that DIBC-alcohol may be more easily conjugated and eliminated in bile. In summary, the metabolic similarities and the difference in systemic exposure to metabolites between these substances observed in the current study support the hypothesis that DIBC might have a lower potential toxicity than that of DIBK. The current study results support that toxicological data on DIBK could be used to characterize the hazards of DIBC.

Resistance to TGF-beta is frequently observed in ovarian cancer, and disrupted TGF-beta/SMAD4 signaling results in the aberrant expression of downstream target genes in the disease. Our previous study showed that ADAM19, a SMAD4 target gene, is downregulated through epigenetic mechanisms in ovarian cancer with aberrant TGF-beta/SMAD4 signaling. In this study, we investigated the mechanism of downregulation of FBXO32, another SMAD4 target gene, and the clinical significance of the loss of FBXO32 expression in ovarian cancer. Expression of FBXO32 was observed in the normal ovarian surface epithelium, but not in ovarian cancer cell lines. FBXO32 methylation was observed in ovarian cancer cell lines displaying constitutive TGF-beta/SMAD4 signaling, and epigenetic drug treatment restored FBXO32 expression in ovarian cancer cell lines regardless of FBXO32 methylation status, suggesting that epigenetic regulation of this gene in ovarian cancer may be a common event. In advanced-stage ovarian tumors, a significant (29.3%; P

It is becoming increasingly evident that discrete genetic alterations in neoplastic cells alone cannot explain multistep carcinogenesis whereby tumor cells are able to express diverse phenotypes during the complex phases of tumor development and progression. The epigenetic model posits that the host microenvironment exerts an initial, inhibitory constraint on tumor growth that is followed by acceleration of tumor progression through complex cell–matrix interactions. This review emphasizes the epigenetic aspects of breast cancer development in light of such interactions between epithelial cells (“seed”) and the tumor microenvironment (“soil”). Our recent research findings suggest that epigenetic perturbations induced by the tumor microenvironment may play a causal role in promoting breast cancer development. It is believed that abrogation of these initiators could offer a promising therapeutic strategy.

Transforming growth factor-beta (TGF-beta)/SMAD signaling is a key growth regulatory pathway often dysregulated in ovarian cancer and other malignancies. Although loss of TGF-beta-mediated growth inhibition has been shown to contribute to aberrant cell behavior, the epigenetic consequence(s) of impaired TGF-beta/SMAD signaling on target genes is not well established. In this study, we show that TGF-beta1 causes growth inhibition of normal ovarian surface epithelial cells, induction of nuclear translocation SMAD4, and up-regulation of ADAM19 (a disintegrin and metalloprotease domain 19), a newly identified TGF-beta1 target gene. Conversely, induction and nuclear translocation of SMAD4 were negligible in ovarian cancer cells refractory to TGF-beta1 stimulation, and ADAM19 expression was greatly reduced. Furthermore, in the TGF-beta1 refractory cells, an inactive chromatin environment, marked by repressive histone modifications (trimethyl-H3K27 and dimethyl-H3K9) and histone deacetylase, was associated with the ADAM19 promoter region. However, the CpG island found within the promoter and first exon of ADAM19 remained generally unmethylated. Although disrupted growth factor signaling has been linked to epigenetic gene silencing in cancer, this is the first evidence demonstrating that impaired TGF-beta1 signaling can result in the formation of a repressive chromatin state and epigenetic suppression of ADAM19. Given the emerging role of ADAMs family proteins in growth factor regulation in normal cells, we suggest that epigenetic dysregulation of ADAM19 may contribute to the neoplastic process in ovarian cancer.

Gradually altered synthetic entities were employed as molecular probes, and arachidonic acid, ADP, human α-thrombin and the Ca 2+ ionophore A23187 as aggregation-inducing agents, in a comprehensive study on the response profile of human blood platelets with an emphasis on the effects of exogenous and increased intracellular Ca 2+ . Corroborating further previous conclusions, some representative carbamoylpiperidine derivatives, at concentrations effecting substantial inhibition of ADP-induced aggregation, failed to retain that effect when 5.0 mM Ca 2+ was introduced into the otherwise identical test medium; reference compounds chlorpromazine and propranolol registered corresponding inhibitory patterns. At increased concentrations the compounds' inhibitory potency was regenerated even in the presence of 5 mM Ca 2+ . In fact, in sufficiently high concentrations, the compounds were even capable of inhibiting aggregation elicited by 15 μM of the ionophore A23187; so did chlorpromazine and propranolol. Another set of congeners revealed the striking sensitivity of ionophore A23187-induced human blood platelet aggregation to the surface active potencies of inhibitor molecules. The loss in inhibitory potency was directly related to the lesser hydrophobic character of the molecule.