PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity.

Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in vivo that contribute to cancer relapse. Patients with chronic lymphocytic leukemia (CLL) have terminally differentiated T cells with an exhausted phenotype and experience low complete response rates after autologous CART therapy. Because PI3K inhibitor therapy is associated with the development of T-cell-mediated autoimmunity, we studied the effects of inhibiting the PI3Kδ and PI3Kγ isoforms during the manufacture of CART cells prepared from patients with CLL. Dual PI3Kδ/γ inhibition normalized CD4/CD8 ratios and maximized the number of CD8+ T-stem cell memory, naive, and central memory T-cells with dose-dependent decreases in expression of the TIM-3 exhaustion marker. CART cells manufactured with duvelisib (Duv-CART cells) showed significantly increased in vitro cytotoxicity against CD19+ CLL targets caused by increased frequencies of CD8+ CART cells. Duv-CART cells had increased expression of the mitochondrial fusion protein MFN2, with an associated increase in the relative content of mitochondria. Duv-CART cells exhibited increased SIRT1 and TCF1/7 expression, which correlated with epigenetic reprograming of Duv-CART cells toward stem-like properties. After transfer to NOG mice engrafted with a human CLL cell line, Duv-CART cells expressing either a CD28 or 41BB costimulatory domain demonstrated significantly increased in vivo expansion of CD8+ CART cells, faster elimination of CLL, and longer persistence. Duv-CART cells significantly enhanced survival of CLL-bearing mice compared with conventionally manufactured CART cells. In summary, exposure of CART to a PI3Kδ/γ inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in vivo.

Building resilient food system amidst COVID-19: Responses and lessons from China.

CONTEXT: The COVID-19 pandemic continues to spread over the world and has heightened concerns over global food security risks. As the first country hit by COVID-19, China has adopted a series of stringent mitigation policies to contain the spread of virus. This has led to food system disruptions due to restrictions on labor and interruption of transport, processing, retailing, and input distribution. OBJECTIVE: The objective of this contribution is to report evidence for initial impacts and resilience of China's food system amid the COVID-19 pandemic and to discuss government's responses as well as long-term efforts that promoted resilience. METHODS: We reviewed a range of publications, government released reports and official information, blogs, and media articles, and whenever possible, we complemented this qualitative information with quantitative data from China's National Bureau of Statistics and finally empirical data obtained from a simulation study. RESULTS AND CONCLUSIONS: We identified China's earlier responses in each key food system activities including ensuring effective logistics of agricultural products and inputs, supporting production and processing, matching supply with demand, and mitigating consumer's income loss. In particular, innovative information and communications technology (ICT) applications along the food system had been highlighted. Coupled with China's long-term efforts in investing in agriculture, building emergency response systems, and adopting governor's responsibility mechanisms, there has been little panic in the food system with largely sufficient supplies and stable prices. In the second quarter of 2020, after registered negative growth in the first quarter, primary agriculture grew by 3.4% and the negative growth of livestock production was narrowed significantly by 8.7 percentage points. Food prices rose by a modest 0.6% and returned to normal after a surge in February 2020. SIGNIFICANCE: We expect that China's experiences on building resilient food systems could improve understanding of the challenges posed by COVID-19 from a retrospective perspective and provide lessons to other countries that are experiencing disruptions in the food systems worldwide. The lessons are also important for strengthening the resilience of food systems over longer time horizons.

Germline mutations: many roles in leukemogenesis.

PURPOSE OF REVIEW: The purpose of this review is to summarize the current understanding of germline mutations as they contribute to leukemia development and progression. We also discuss how these new insights may help improve clinical management of germline mutations associated with leukemia. RECENT FINDINGS: Germline mutations may represent important initial mutations in the development of leukemia where interaction with somatic mutations provide further hits in leukemic progression. In addition, germline mutations may also contribute to leukemogenesis by impacting bone marrow stem-cell microenvironment and immune cell development and function. SUMMARY: Leukemia is characterized by the clonal expansion of malignant cells secondary to somatic or germline mutations in a variety of genes. Understanding somatic mutations that drive leukemogenesis has drastically improved our knowledge of leukemia biology and led to novel therapeutic strategies. Advances have also been made in identifying germline mutations that may affect leukemic development and progression. This review will discuss the biological and clinical relationship of germline mutations with clonal hematopoiesis, bone marrow microenvironment, and immunity in the progression of leukemia.

Making health insurance pro-poor: evidence from a household panel in rural China.

BACKGROUND: In 2002, China launched the largest public health insurance scheme in the world, the New Cooperative Medical Scheme (NCMS). It is intended to enable rural populations to access health care services, and to curb medical impoverishment. Whether the scheme can reach its equity goals depends on how it is used, and by whom. Our goal is to shed light on whether and how income levels affect the ability of members to reap insurance benefits. METHODS: We exploit primary panel data consisting of a complete census (over 3500 individuals) in three villages in Puding County, Guizhou province, collected in 2004, 2006, 2009 and 2011. Data was collected during in-person interviews with household member(s). The data include yearly gross and net medical expenses for all individuals, and socio-economic information. We apply probit, ordinary least squares, and tobit multivariate regression analyses to the three waves in which NCMS was active (2006, 2009 and 2011). Explained variables include obtainment, levels and rates of NCMS reimbursement. Household income is the main explanatory variable, with household- and individual-level controls. We restrict samples to rule out self-selection, and exploit the 2009 NCMS reform to highlight equity-enhancing features of insurance. RESULTS: Prior to 2009 reforms, higher income in our sample was statistically significantly related to higher probability of obtaining reimbursement, as well as higher levels and rates of reimbursement. These relations all disappear after the reform, suggesting lower-income households were better able to reap insurance benefits after the scheme was reformed. Regression results suggest this is partly explained by reimbursement for chronic diseases. CONCLUSIONS: The post-reform NCMS distributed benefits more equitably in our study area. Making health insurance pro-poor may require a focus on outpatient costs, credit constraints and chronic diseases, rather than catastrophic illnesses.

The triple benefits of slimming and greening the Chinese food system.

The Chinese food system has undergone a transition of unprecedented speed, leading to complex interactions with China's economy, health and environment. Structural changes experienced by the country over the past few decades have boosted economic development but have worsened the mismatch between food supply and demand, deteriorated the environment, driven obesity and overnutrition levels up, and increased the risk for pathogen spread. Here we propose a strategy for slimming and greening the Chinese food system towards sustainability targets. This strategy takes into account the interlinkages between agricultural production and food consumption across the food system, going beyond agriculture-focused perspectives. We call for a food-system approach with integrated analysis of potential triple benefits for the economy, health and the environment, as well as multisector collaboration in support of evidence-based policymaking.

B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12.

Immunotherapies have revolutionized the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but the duration of responses is still sub-optimal. We sought to identify mechanisms of immune suppression in B-ALL and strategies to overcome them. Plasma collected from children with B-ALL with measurable residual disease after induction chemotherapy showed differential cytokine expression, particularly IL-7, while single-cell RNA-sequencing revealed the expression of genes associated with immune exhaustion in immune cell subsets. We also found that the supernatant of leukemia cells suppressed T-cell function ex vivo. Modeling B-ALL in mice, we observed an altered tumor immune microenvironment, including compromised activation of T-cells and dendritic cells (DC). However, recombinant IL-12 (rIL-12) treatment of mice with B-ALL restored the levels of several pro-inflammatory cytokines and chemokines in the bone marrow and increased the number of splenic and bone marrow resident T-cells and DCs. RNA-sequencing of T-cells isolated from vehicle and rIL-12 treated mice with B-ALL revealed that the leukemia-induced increase in genes associated with exhaustion, including Lag3, Tigit, and Il10, was abrogated with rIL-12 treatment. In addition, the cytolytic capacity of T-cells co-cultured with B-ALL cells was enhanced when IL-12 and blinatumomab treatments were combined. Overall, these results demonstrate that the leukemia immune suppressive microenvironment can be restored with rIL-12 treatment which has direct therapeutic implications.

The Zoonotic diseases, agricultural production, and impact channels: Evidence from China.

The outbreak and wide spread of COVID-19 poses a new threat to global food security. This paper aims to address two important policy related issues, that is which agricultural subsector suffers more under zoonotic diseases and how do zoonotic diseases affect these subsectors. Using provincial panel data of 24 main farm commodities in China from 2002 to 2017, this paper identifies the impacts of zoonotic diseases and projects the potential disruption of COVID-19 to agricultural output in China under three scenarios. The main findings are as follows. First, zoonotic diseases have adverse impacts on almost all the farm commodities, while livestock on average suffers more than crops. Second, zoonotic diseases affect these subsectors mainly through the channel of adverse shocks on total factor productivity (TFP). Third, while a few subsectors can find a way to offset part of the TFP loss by applying more input, most subsectors suffer from both input reduction and TFP loss. Fourth, the spread of COVID-19 is projected to lower the growth rates of China's crop and livestock sector by 1.1%-2.3% and 1.3%-2.6%, with TFP loss by 1.1%-2.0% and 1.4%-2.7%, respectively, in 2020. This paper then discusses several policy implications for mitigating the negative impacts of COVID-19 on agricultural production in China and elsewhere.

Fire lines as fault lines: increased trade barriers during the COVID-19 pandemic further shatter the global food system.

In this opinion piece, we highlight that trade barriers established during COVID-19 as "fire lines" to prevent cross-border transmission of the pandemic could become "fault lines" that demolish the global food system. We review restrictions on both international agricultural exports and imports, especially unilateral border controls such as import refusals and alerts, in previous epidemics and arising with two novel features amid COVID-19. Institutional causes to pervasive trade barriers in epidemics that are embedded in the WHO-WTO coordination scheme have been discussed. In the meantime, discussions on potential economic outcomes and policy recommendations have been provided.

The quiet revolution in Asia's rice value chains.

There is a rapid transformation afoot in the rice value chain in Asia. The upstream is changing quickly-farmers are undertaking capital-led intensification and participating in burgeoning markets for land rental, fertilizer and pesticides, irrigation water, and seed, and shifting from subsistence to small commercialized farms; in some areas landholdings are concentrating. Midstream, in wholesale and milling, there is a quiet revolution underway, with thousands of entrepreneurs investing in equipment, increasing scale, diversifying into higher quality, and the segments are undergoing consolidation and vertical coordination and integration. Mills, especially in China, are packaging and branding, and building agent networks in wholesale markets, and large mills are building direct relationships with supermarkets. The downstream retail segment is undergoing a "supermarket revolution," again with the lead in change in China. In most cases the government is not playing a direct role in the market, but enabling this transformation through infrastructural investment. The transformation appears to be improving food security for cities by reducing margins, offering lower consumer rice prices, and increasing quality and diversity of rice. This paper discusses findings derived from unique stacked surveys of all value chain segments in seven zones, more and less developed, around Bangladesh, China, India, and Vietnam.

Prevention of losses for hog farmers in China: insurance, on-farm biosecurity practices, and vaccination.

Using agricultural household survey data and claim records from insurers in China, this paper analyzes hog producers' choice of the ways to prevent possible losses and identifies the relationships among biosecurity practices, vaccination, and hog insurance. By combining one probit and two structural equations, we adopt three-stage estimations by a mixed-process model to obtain results. The findings indicate that biosecurity practices provide the basic infrastructure for operating pig farms and complement both the usage of quality vaccines and the uptake of hog insurance. In addition, there is a strong substitution relationship between the quality of vaccine and the demand for hog insurance. Hog farmers that implement better biosecurity practices are more likely to seek high-quality vaccines or buy into hog insurance schemes, but not both. For those households with hog insurance, better biosecurity status, better management practices, and higher-quality vaccines significantly help to reduce loss ratios. However, we also find a moral hazard effect in that higher premium expenditures by the insured households might induce larger loss ratios.