cDC2 plasticity and acquisition of a DC3-like phenotype mediated by IL-6 and PGE2 in a patient-derived colorectal cancer organoids model

Metastatic colorectal cancer (CRC) is highly resistant to therapy and prone to recur. The tumor-induced local and systemic immunosuppression allows cancer cells to evade immunosurveillance, facilitating their proliferation and dissemination. Dendritic cells (DCs) are required for the detection, processing, and presentation of tumor antigens, and subsequently for the activation of antigen-specific T cells to orchestrate an effective antitumor response. Notably, successful tumors have evolved mechanisms to disrupt and impair DC functions, underlining the key role of tumor-induced DC dysfunction in promoting tumor growth, metastasis initiation, and treatment resistance. Conventional DC type 2 (cDC2) are highly prevalent in tumors and have been shown to present high phenotypic and functional plasticity in response to tumor-released environmental cues. This plasticity reverberates on both the development of antitumor responses and on the efficacy of immunotherapies in cancer patients. Uncovering the processes, mechanisms, and mediators by which CRC shapes and disrupts cDC2 functions is crucial to restoring their full antitumor potential. In this study, we use our recently developed 3D DC-tumor co-culture system to investigate how patient-derived primary and metastatic CRC organoids modulate cDC2 phenotype and function. We first demonstrate that our collagen-based system displays extensive interaction between cDC2 and tumor organoids. Interestingly, we show that tumor-corrupted cDC2 shift toward a CD14+ population with defective expression of maturation markers, an intermediate phenotype positioned between cDC2 and monocytes, and impaired T-cell activating abilities. This phenotype aligns with the newly defined DC3 (CD14(+) CD1c(+) CD163(+)) subset. Remarkably, a comparable population was found to be present in tumor lesions and enriched in the peripheral blood of metastatic CRC patients. Moreover, using EP2 and EP4 receptor antagonists and an anti-IL-6 neutralizing antibody, we determined that the observed phenotype shift is partially mediated by PGE2 and IL-6. Importantly, our system holds promise as a platform for testing therapies aimed at preventing or mitigating tumor-induced DC dysfunction. Overall, our study offers novel and relevant insights into cDC2 (dys)function in CRC that hold relevance for the design of therapeutic approaches

Netherlands

The Netherlands traditionally had ample early retirement possibilities. Several reforms introduced from the late 1990s onward contributed to the successful reversal of this early exit trend. As a result, in 2018, employees o

Dual-Earner Family Policies at Work for Single-Parent Families

Family dynamics are changing and single-parent families are becoming more common across countries. In their flagship report “Progress of the World’s Women, 2019–2020,” UN Women (2019) demonstrated that, contrary to popular belief, couples with children do not constitute a majority of all families, but rather there are many different types of families. Single parenthood is considered a “new social risk” in poverty and inequality (Bonoli, 2013). Therefore, policy makers and legislators have designed targeted policy specifically for single parents, such as targeted child benefits to single parents. In addition, legislation and social policy have been designed and implemented specifically for single parents, such as child support and family law such as child custody and shared residence. This study takes a different approach, based on the universalist argument that without adequate social protection that benefits all families, those families that are more vulnerable are often hit the hardest. We focus on family policies, and specifically we examine whether and to what extent single parents benefit from the same family policies that are available to all families with children

Living on social assistance with chronic illness: Buffering and undermining features to well-being

<p>Abstract</p> <p>Background</p> <p>In Sweden, the social security and sickness insurance systems are comprehensive and aim to provide people whose illness prevents them from earning their own living, with either sickness benefits or disability pension. Some, however, are not entitled to these benefits or receive social insurance benefits at a level too low for subsistence, and are referred to social assistance. The purpose of this study was to explore in depth how social assistance recipients with chronic illness perceive and respond to the experience of living on social assistance.</p> <p>Methods</p> <p>Seventeen in-depth interviews were carried out with chronically ill people who had received social assistance for several years. Grounded theory informed the design of the study.</p> <p>Results</p> <p>The study showed that different strategies (living one day at a time, taking steps forwards and backwards and making attempts to find ways out of the situation) were employed by social assistance recipients to maintain or improve their well-being. Contextual features like the prevailing welfare system, public services and the local neighbourhood could buffer or undermine these strategies and their overall well-being. These features together influenced how interviewees perceived their situation, the possible ways out of the situation and the consequences for their well-being.</p> <p>Conclusion</p> <p>From this study it is evident that the way in which individuals on social assistance interact with services and how they are treated by professionals plays an important role in their well-being, in combination with what kind of help and support is available for recipients through the welfare system. In this respect, persons living on social assistance with chronic illness are particularly vulnerable. This study suggests that more effort should be made to find long term solutions concerning income support, rehabilitation and other services provided to this group.</p

National strategy for palliative care of severely ill and dying people and their relatives in pandemics (PallPan) in Germany - study protocol of a mixed-methods project

BACKGROUND In the SARS-CoV-2 pandemic, general and specialist Palliative Care (PC) plays an essential role in health care, contributing to symptom control, psycho-social support, and providing support in complex decision making. Numbers of COVID-19 related deaths have recently increased demanding more palliative care input. Also, the pandemic impacts on palliative care for non-COVID-19 patients. Strategies on the care for seriously ill and dying people in pandemic times are lacking. Therefore, the program 'Palliative care in Pandemics' (PallPan) aims to develop and consent a national pandemic plan for the care of seriously ill and dying adults and their informal carers in pandemics including (a) guidance for generalist and specialist palliative care of patients with and without SARS-CoV-2 infections on the micro, meso and macro level, (b) collection and development of information material for an online platform, and (c) identification of variables and research questions on palliative care in pandemics for the national pandemic cohort network (NAPKON). METHODS Mixed-methods project including ten work packages conducting (online) surveys and qualitative interviews to explore and describe i) experiences and burden of patients (with/without SARS-CoV-2 infection) and their relatives, ii) experiences, challenges and potential solutions of health care professionals, stakeholders and decision makers during the SARS-CoV-2 pandemic. The work package results inform the development of a consensus-based guidance. In addition, best practice examples and relevant literature will be collected and variables for data collection identified. DISCUSSION For a future \textquotedblpandemic preparedness\textquotedbl national and international recommendations and concepts for the~care of severely ill and dying people are necessary considering both generalist and specialist palliative care in the home care and inpatient setting

A New Algorithm for the Unbalanced Meet-in-the-Middle Problem

A collision search for a pair of $n$-bit unbalanced functions (one is $R$ times more expensive than the other) is an instance of the meet-in-the-middle problem, solved with the familiar standard algorithm that follows the tradeoff $TM=N$, where $T$ and $M$ are time and memory complexities and $N=2^n$. By combining two ideas, unbalanced interleaving and Oorschot-Wiener parallel collision search, we construct an alternative algorithm that follows $T^2 M = R^2 N$, where $M\le R$. Among others, the algorithm solves the well-known open problem: how to reduce the memory of unbalanced collision search

Simple Nudges for Better Password Creation

Recent security breaches have highlighted the consequences of reusing passwords across online accounts. Recent guidance on password policies by the UK government recommend an emphasis on password length over an extended character set for generating secure but memorable passwords without cognitive overload. This paper explores the role of three nudges in creating website-specific passwords: financial incentive (present vs absent), length instruction (long password vs no instruction) and stimulus (picture present vs not present). Mechanical Turk workers were asked to create a password in one of these conditions and the resulting passwords were evaluated based on character length, resistance to automated guessing attacks, and time taken to create the password. We found that users created longer passwords when asked to do so or when given a financial incentive and these longer passwords were harder to guess than passwords created with no instruction. Using a picture nudge to support password creation did not lead to passwords that were either longer or more resistant to attacks but did lead to account-specific passwords

New Attacks on the Concatenation and XOR Hash Combiners

We study the security of the concatenation combiner $H_1(M) \| H_2(M)$ for two independent iterated hash functions with $n$-bit outputs that are built using the Merkle-Damgård construction. In 2004 Joux showed that the concatenation combiner of hash functions with an $n$-bit internal state does not offer better collision and preimage resistance compared to a single strong $n$-bit hash function. On the other hand, the problem of devising second preimage attacks faster than $2^n$ against this combiner has remained open since 2005 when Kelsey and Schneier showed that a single Merkle-Damgård hash function does not offer optimal second preimage resistance for long messages. In this paper, we develop new algorithms for cryptanalysis of hash combiners and use them to devise the first second preimage attack on the concatenation combiner. The attack finds second preimages faster than $2^n$ for messages longer than $2^{2n/7}$ and has optimal complexity of $2^{3n/4}$. This shows that the concatenation of two Merkle-Damgård hash functions is not as strong a single ideal hash function. Our methods are also applicable to other well-studied combiners, and we use them to devise a new preimage attack with complexity of $2^{2n/3}$ on the XOR combiner $H_1(M) \oplus H_2(M)$ of two Merkle-Damgård hash functions. This improves upon the attack by Leurent and Wang (presented at Eurocrypt 2015) whose complexity is $2^{5n/6}$ (but unlike our attack is also applicable to HAIFA hash functions). Our algorithms exploit properties of random mappings generated by fixing the message block input to the compression functions of $H_1$ and $H_2$. Such random mappings have been widely used in cryptanalysis, but we exploit them in new ways to attack hash function combiners

Sozialstaatliche Kürzungspolitik in Deutschland: Nur eine Mär? Eine quantitative Gesetzgebungsanalyse 1974–2014

Quantitative analyses on welfare state dynamics have to cope with the “dependent variable problem”, as studies on social spending reach different conclusions than analyses of replacement rate data. This article suggests a way around this problem by presenting results from a fine-grained analysis of welfare state legislation in Germany between 1974 and 2014. We show that the German welfare state has seen both cuts and expansions occur in all decades. Moreover, we show by means of a regression analysis that partisan politics play a role. Supporting the “Nixon-in-China”-thesis, social democratic governments are associated with a higher probability of cutbacks – especially in times of budgetary pressure – whereas expansions are more likely under Christian democratic governments