Cell death and cytokine-mediated inflammatory responses to glucose deprivation in cancer cells

[eng] Metabolic alterations in cancer cells are primarily caused by oncogenic mutations and cancer cells are more dependent on glucose compared to non-transformed tissue. Targeting the cancer metabolism opens up a new strategy for anti-cancer therapy. In order to make drugs more efficient and applicable in the clinic, it is necessary to fully investigate the cancer cell metabolism, especially of how cancer cells die upon glucose deprivation and more importantly, the consequences on the surrounding tissue when modifying or interfering with the metabolism. The unfolded protein response (UPR) is an intracellular stress response which is induced upon glucose deprivation. The activation of the three branches of the UPR facilitates pro-survival responses, however, chronic exposure to intra- or extracellular stress results in a switch towards a pro-death UPR response. The UPR is also described to be involved in pro-inflammatory responses due to the induction of cytokines and chemokines in several cell lines. Therefore, the release of cytokines upon glucose deprivation could facilitate the infiltration or exclusion of immune cells. We hypothesized that cancer cells die in an UPR dependent manner and that cancer cells release inflammatory cytokines upon glucose deprivation, which promote the infiltration of immune cells. We found that HeLa cells exposed to glucose deprivation, died in a TRAIL receptor 1 (DR4) and 2 (DR5) dependent manner, which was mediated by the activation transcription factor 4 (ATF4). Furthermore, we found the release of pro-tumorigenic cytokines such as interleukin-8 (IL-8), interleukin-6 (IL-6) and the leukemia inhibitory factor (LIF) from glucose deprived cancer cells as well as upon treatment with anti-metabolic drugs. We found that IL 6 and IL-8 but not LIF were regulated by ATF4 and p65 upon glucose deprivation. Moreover, the conditioned media of glucose deprived A549 promoted the migration of macrophage-like THP-1 cells as well as primary B cells and neutrophils isolated from human blood. These findings are important, since interfering with the cancer metabolism by using anti metabolic drugs could suppress the anti-tumorigenic effect of these drugs by promote pro-tumorigenic responses

In the hunger games, the winner takes everything

Entosis is an atypical form of cell death that occurs when a cell engulfs and kills another cell. A recent article by Overholtzer and colleagues indicates that glucose deprivation promotes entosis. AMPK activation in the loser cells triggers their engulfment and elimination by winner cells, which endure starvation

Gesundheit wohnungsloser Menschen während der COVID-19-Pandemie [Health of homeless individuals during the COVID-19 pandemic]

The living situation and health of homeless people differs from the general population in many ways. It is reasonable to assume that the homeless population has been particularly vulnerable during the coronavirus disease 2019 (COVID-19) pandemic. This narrative review will summarize the current literature on the health and care of homeless people during the COVID-19 pandemic. The literature research was performed between December 2022 and February 2023. In addition to the current national and international literature, findings from the "National Survey on the Psychiatric and Somatic Health of Homeless Individuals" (NAPSHI study) will be synopsized, examining psychiatric and somatic diseases as well as the care for homeless people in Germany. Homeless individuals are often mentally and physically ill and have limited access to the regular medical care system. Facilities with group rooms and dormitories pose a risk for outbreaks during the COVID-19 pandemic. As suspected, evidence of Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV‑2) infections emerged more frequently in homeless individuals than in the general population during the pandemic. Many of the infected individuals were asymptomatic. High rates of those unknowingly infected homeless individuals may have contributed to the spread of the viral disease. However, uncontrolled COVID-19 outbreaks, as feared by some researchers at the beginning of the pandemic, were not observed. Die Lebenssituation und die Gesundheit wohnungsloser Menschen unterscheiden sich in vielerlei Hinsicht von denen der Allgemeinbevölkerung. Die Vermutung liegt nahe, dass es sich bei wohnungslosen Menschen um eine besonders vulnerable Personengruppe während der Coronavirus-Disease-2019(COVID-19)-Pandemie handelt. In dieser narrativen Übersichtsarbeit soll die aktuelle Literatur zur Gesundheit und Versorgung von wohnungslosen Menschen während der COVID-19-Pandemie zusammengefasst werden. Recherchiert wurde zwischen Dezember 2022 und Februar 2023. Neben der aktuellen nationalen und internationalen Literatur sollen insbesondere die Ergebnisse des „National survey on psychiatric and somatic health of homeless individuals“ (NAPSHI-Studie) synoptisch dargestellt werden; diese untersucht psychische und somatische Erkrankungen sowie die Versorgung wohnungsloser Menschen in Deutschland. Wohnungslose Menschen sind häufig psychisch und somatisch erkrankt und haben einen eingeschränkten Zugang zum medizinischen Regelsystem. Versorgungseinrichtungen mit Gruppenräumen und Schlafsälen stellen ein Risiko für ein Ausbruchsgeschehen in der COVID-19-Pandemie dar. Wie vermutet, zeigten sich im Verlauf der Pandemie bei wohnungslosen Menschen häufiger als in der Allgemeinbevölkerung Hinweise für Severe Acute Respiratory Syndrome Coronavirus Type 2(SARS-CoV‑2)-Infektionen, viele davon schienen allerdings asymptomatisch zu verlaufen. Eine hohe Rate an unwissentlich infizierten wohnungslosen Menschen könnte zur Verbreitung der Viruserkrankung beigetragen haben. Trotzdem war ein unkontrolliertes COVID-19-Ausbruchsgeschehen, vor dem einige Wissenschaftler:innen zu Beginn der Pandemie warnten, nicht zu beobachten

TRAIL receptors promote constitutive and inducible IL-8 secretion in non-small cell lung carcinoma

Interleukin-8 (IL-8/CXCL8) is a pro-angiogenic and pro-inflammatory chemokine that plays a role in cancer development. Non-small cell lung carcinoma (NSCLC) produces high amounts of IL-8, which is associated with poor prognosis and resistance to chemo-radio and immunotherapy. However, the signaling pathways that lead to IL-8 production in NSCLC are unresolved. Here, we show that expression and release of IL-8 are regulated autonomously by TRAIL death receptors in several squamous and adenocarcinoma NSCLC cell lines. NSCLC constitutively secrete IL-8, which could be further enhanced by glucose withdrawal or by treatment with TRAIL or TNF alpha. In A549 cells, constitutive and inducible IL-8 production was dependent on NF-kappa B and MEK/ERK MAP Kinases. DR4 and DR5, known regulators of these signaling pathways, participated in constitutive and glucose deprivation-induced IL-8 secretion. These receptors were mainly located intracellularly. While DR4 signaled through the NF-kappa B pathway, DR4 and DR5 both regulated the ERK-MAPK and Akt pathways. FADD, caspase-8, RIPK1, and TRADD also regulated IL-8. Analysis of mRNA expression data from patients indicated that IL-8 transcripts correlated with TRAIL, DR4, and DR5 expression levels. Furthermore, TRAIL receptor expression levels also correlated with markers of angiogenesis and neutrophil infiltration in lung squamous carcinoma and adenocarcinoma. Collectively, these data suggest that TRAIL receptor signaling contributes to a pro-tumorigenic inflammatory signature associated with NSCLC

Prevalence and Factors Associated with Fear of COVID-19 Among Homeless Individuals During the COVID-19 Pandemic: Evidence from the Hamburg Survey of Homeless Individuals.

PURPOSE: To clarify the prevalence and determinants of fear of COVID-19 among homeless individuals during the COVID-19 pandemic. PATIENTS AND METHODS: Data were taken from the Hamburg survey of homeless individuals (n=150) covering homeless adults in Hamburg, Germany. Multiple linear regressions were used. Beyond sociodemographic and lifestyle-related independent variables, COVID-19-related factors were also used as independent variables. RESULTS: In sum, 56.2% of homeless individuals reported no fear of COVID-19, 23.8% reported a little fear of COVID-19, 9.2% reported some fear of COVID-19 and 10.8% reported severe fear of COVID-19. Regressions showed that an increased fear of COVID-19 was significantly associated with younger age (β=-.01, p<0.05), absence of chronic alcohol consume (β=-.55, p<0.01), an increased perceived own risk of getting infected with the coronavirus one day (β=0.42, p<0.001) and a higher agreement that a diagnosis of the coronavirus would ruin his/her life (β=0.13, p<0.01). CONCLUSION: Given the poor hygienic conditions and their increased vulnerability, data surprisingly suggest a quite low fear of COVID-19 among homeless individuals. Efforts may be beneficial which contribute to thinking rationally about COVID-19 among homeless people, since low levels of fear of COVID-19 may contribute to careless behavior and can lead to super-spreading events

Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells

Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation

Loneliness among Homeless Individuals during the First Wave of the COVID-19 Pandemic.

The feeling of loneliness is a major public health concern associated with multiple somatic and psychiatric illnesses. Studies have shown increasing incidence of loneliness in the general population during the first wave of the COVID-19 pandemic. Homeless individuals are a particularly vulnerable group; however, little is known about loneliness among homeless individuals. We therefore aimed to examine the prevalence of loneliness among homeless individuals during the pandemic. Furthermore, we estimated the association between loneliness and sociodemographic and lifestyle factors, as well as the self-perceived risk of contracting COVID-19. Data from the Hamburg survey of homeless individuals were used, including 151 homeless individuals that were recruited in spring of 2020. Loneliness was measured by the 3- item version of the UCLA-3 Loneliness Scale. To summarize, 48.5% of the participants experienced loneliness. Multiple linear regressions showed increased loneliness to be associated with male gender (β = 1.07, p = 0.01), being single (β = 1.33, p = 0.00), originating from Germany (β = 1.48, p = 0.00), high frequency of sharing a sleeping space with more than three people (β = 0.42, p = 0.02) and a higher self-perceived risk of contracting COVID-19 (β = 0.41, p = 0.02). On the contrary, there was no association of loneliness with age, educational level, chronic alcohol consumption or frequently sharing a sleeping space. In conclusion, the magnitude of loneliness among homeless individuals during the pandemic was highlighted. Description of factors determining loneliness may help to identify homeless individuals at risk

Seroprevalence of arthropod-borne bacterial infections in homeless individuals in Hamburg in 2020

PURPOSE: The number of homeless people in Germany is steadily increasing. Due to their often precarious living conditions, this specific population may be increasingly exposed to ectoparasites that can transmit various pathogens. To assess the prevalence and thus the risk of such infections, we analyzed the seropositivity of rickettsiosis, Q fever, tularemia and bartonellosis in homeless individuals. METHODS: A total of 147 homeless adults from nine shelters in Hamburg, Germany, were included. The individuals underwent questionnaire-based interviewing, physical examination, and venous blood was drawn between May and June 2020. Blood samples were analyzed for antibodies against rickettsiae (Rickettsia typhi and R. conorii), Coxiella burnetii, Francisella tularensis and bartonellae. RESULTS AND CONCLUSION: A very low seroprevalence of R. typhi and F. tularensis infection was found (0-1%), while antibodies against R. conorii and C. burnetii were more common (7% each), followed by a relatively high seroprevalence of 14% for bartonellosis. Q fever seroprevalence was associated with the country of origin, whereas bartonellosis seroprevalence was associated with the duration of homelessness. Preventive measures targeting ectoparasites, especially body lice, should be put in place continuously

Fear of COVID-19 among homeless individuals in Germany in mid-2021.

AIMS: To investigate the prevalence and the correlates of fear of COVID-19 among homeless individuals. METHODS: We used data from the "national survey on psychiatric and somatic health of homeless individuals during the COVID-19 pandemic" (NAPSHI-study) which took place in several large cities in Germany in Mid-2021 (n = 666 in the analytical sample). Mean age equaled 43.3 years (SD: 12.1 years), ranging from 18 to 80 years. Multiple linear regressions were performed. RESULTS: In our study, 70.9% of the homeless individuals reported no fear of COVID-19. Furthermore, 14.0% reported a little fear of COVID-19, 8.4% reported some fear of COVID-19 and 6.7% reported severe fear of COVID-19. Multiple linear regressions revealed that fear of COVID-19 was higher among individuals aged 50-64 years (compared to individuals aged 18-29 years: β = 0.28, p < 0.05), among individuals with a higher perceived own risk of contracting the coronavirus 1 day (β = 0.28, p < 0.001) as well as among individuals with a higher agreement that a diagnosis of the coronavirus would ruin his/her life (β = 0.15, p < 0.001). CONCLUSIONS: Only a small proportion of homeless individuals reported fear of COVID-19 in mid-2021 in Germany. Such knowledge about the correlates of higher levels of fear of COVID-19 may be helpful for addressing certain risk groups (e.g., homeless individuals aged 50-64 years). In a further step, avoiding extraordinarily high levels of fear of COVID-19 may be beneficial to avoid irrational thinking and acting regarding COVID-19 in this group

Determinants of health-related quality of life (HRQoL) among homeless individuals during the COVID-19 pandemic

OBJECTIVE: Thus far, there is very limited knowledge regarding homeless individuals during the COVID-19 pandemic, particularly related to the health-related quality of life (HRQoL). Thus, our aim was to evaluate HRQoL and to clarify the determinants of HRQoL among homeless individuals during the COVID-19 pandemic in Germany. METHODS: Data were taken from the national survey on psychiatric and somatic health of homeless individuals during the COVID-19 pandemic-NAPSHI (n = 616). The established EQ-5D-5L was used to quantify problems in five health dimensions, and its visual analogue scale (EQ-VAS) was used to record self-rated health status. Sociodemographic factors were included in regression analysis. RESULTS: Pain/discomfort was the most frequently reported problem (45.3%), thereafter anxiety/depression (35.9%), mobility (25.4%), usual activities (18.5%) and self-care (11.4%). Average EQ-VAS score was 68.97 (SD: 23.83), and the mean EQ-5D-5L index was 0.85 (SD: 0.24). Regressions showed that higher age and having a health insurance were associated with several problem dimensions. Being married was associated with higher EQ-VAS scores. CONCLUSIONS: Overall, our study findings showed a quite high HRQoL among homeless individuals during the COVID-19 pandemic in Germany. Some important determinants of HRQoL were identified (e.g., age or marital status). Longitudinal studies are required to confirm our findings