Search Results (18)

CD8+ T lymphocytes (CTLs) act as serial killers of infected or malignant cells by releasing large amounts of interferon-gamma (IFNγ) and granzymes. Although IFNγ is a pleiotropic cytokine with diverse immunomodulatory functions, its precise spatiotemporal regulation and role in CTL-mediated cytotoxicity remain incompletely understood. Using wild-type and granzyme B-mTFP knock-in mice, we employed a combination of in vitro approaches, including T cell isolation and culture, plate-bound anti-CD3e stimulation, degranulation assays, flow cytometry, immunofluorescence, and structured illumination microscopy, to investigate IFNγ dynamics in CTLs. IFNγ expression in CTLs was rapid, transient, and strictly dependent on T cell receptor (TCR) activation. We identified two functionally distinct IFNγ-producing subsets: IFNγ^high (IFNγ^hi) and IFNγ^low (IFNγ^lo) CTLs. IFNγ^hi CTLs exhibited an effector/effector memory phenotype, significantly elevated CD107a surface expression (a marker of lytic granule exocytosis), and higher colocalization with cis-Golgi and granzyme B compared to IFNγ^lo CTLs. Furthermore, CRTAM, an early activation marker, correlated with IFNγ expression in naive CTLs. Our findings establish a link between elevated IFNγ production and enhanced CTL cytotoxicity, implicating CRTAM as a potential regulator of early CTL activation and IFNγ induction. These insights provide a foundation for optimizing T cell-based immunotherapies against infections and cancers. Full article

“Bluebeard” (ATU 321: Maiden-Killer), a fairy tale about a wealthy noble man and serial killer, is the most gruesome of Charles Perrault’s fairy tales. Bluebeard epitomizes evil and horror. In Perrault’s tale, Bluebeard’s evilness is linked to patriarchy and power, as symbolized by the villain’s iconic blue beard. Historically linked to Henry VIII (1491–1547), King of England, Bluebeard has also been associated with Breton commander Gilles de Rais who was hanged for sorcery and satanic abuse. This article examines how contemporary francophone “Bluebeard” variants refashion and redefine evil and whether they contain any new morals linked to evilness. Do they depict Bluebeard as a satanic, intrinsic force of evil or do they portray him in a less Manichean manner, as contemporary tales tend to do with monsters? Starting with Perrault’s famous tale, this article reveals how Bluebeard, the evil mass murderer figure and polygamist, is recast in a variety of contemporary francophone texts from Morocco, Belgium and France, with retellings by Michel Tournier (1981), Marie Darrieussecq (2002), La Barbe Bleue (Bluebeard) (2009), Amélie Nothomb (2012), Tahar Ben Jelloun (2014), Jacqueline Kelen (2014), and Cécile Coulon (2015). These modern variants illustrate Elliott Oring’s ideas about comparison and cultural context (see Oring 1986). A discussion of various French contemporary versions with a special emphasis of Ben Jelloun’s Moroccan retelling of “Bluebeard” open avenues for cross-cultural dialogue, highlighting how this tale evolves to fit different cultural contexts and continues to resonate today. Full article

This article considers the formal and critical consequences of organizing an aesthetic corpus around the philosophical concept of the fragment via a reading of Aryan Kaganof’s “Ten Monologues from the Lives of the Serial Killers” (1994). This experimental video sets spoken accounts from the perspective of the likes of Ted Bundy and Charles Manson alongside grainy, ambiguous imagery. Instead of thematic meditations on violence, the monologues circle around quasi-nostalgic reflections on the past and the nature of identity. The film frustrates any language of formal analysis that would rely on accounting for what is present in the film, instead proposing a sympathy with poststructuralism’s efforts at displacing the metaphysics of appearance. Violence is not what resides ready-made within the work, nor is it reducible to the realm of the visible or the audible, but is an unstable process bound up with the act of reading itself. The fragment as a formal problem holds out the abstract, general notion of a break in ways that compel a rethinking of violence as something impersonal, rhythmic, and grammatical. Full article

Tumor cells rely heavily on glycolysis to meet their high metabolic demands. While this results in nutrient deprivation within the tumor microenvironment and has negative effects on infiltrating immune cells such as natural killer (NK) cells, it also creates a potential target for cancer therapies. Here we use Glupin, an inhibitor of glucose transporters, to study the effect of limited glucose uptake on NK cells and their anti-tumor functions. Glupin treatment effectively inhibited glucose uptake and restricted glycolysis in NK cells. However, acute treatment had no negative effect on NK cell cytotoxicity or cytokine production. Long-term restriction of glucose uptake via Glupin treatment only delayed NK cell proliferation, as they could switch to glutaminolysis as an alternative energy source. While IFN-γ production was partially impaired, long-term Glupin treatment had no negative effect on degranulation. Interestingly, the serial killing activity of NK cells was even slightly enhanced, possibly due to changes in NAD metabolism. This demonstrates that NK cell cytotoxicity is remarkably robust and insensitive to metabolic disturbances, which makes cellular metabolism an attractive target for immune-mediated tumor therapies. Full article

Glypican-3 (GPC3) is an oncofetal antigen that is highly expressed in multiple solid tumors, including hepatocellular carcinoma, and is barely expressed in adult normal tissues except the placenta. NKp46 activation receptor is expressed in all-natural killer (NK) cells, including tumor-infiltrating NK cells. FLEX-NK^TM is a platform for the production of tetravalent multifunctional antibody NK cell engagers (NKE). CYT-303 was designed using the FLEX-NK scaffold, incorporating a novel humanized NKp46 binder that does not induce NKp46 internalization and a humanized GPC3 binder that targets the membrane-proximal lobe to mediate NK cell-redirected killing of HCC tumors. CYT-303 shows sub-nanomolar binding affinities to both GPC3 and NKp46. CYT-303 was highly potent and effective in mediating NK cell-redirected cytotoxicity against multiple HCC tumor cell lines and tumor spheroids. More interestingly, it can reverse the dysfunction induced in NK cells following repeated rounds of serial killing of tumors. It also mediated antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity against GPC3-expressing HCC tumors. In vivo, CYT-303 showed no toxicity or cytokine release in cynomolgus monkeys up to the highest dose (60 mg/kg), administered weekly by intravenous infusion for 28 days. These results demonstrate the potential of CYT-303 to be a safe and effective therapy against HCC. Full article

Tumor cells often have very high energy demands. Inhibition of glucose uptake is therefore a possible approach to limit the proliferation and survival of transformed cells. However, immune cells also require energy to initiate and to maintain anti-tumor immune reactions. Here, we investigate the effect of Glutor, an inhibitor of glucose transporters, on the function of human Natural Killer (NK) cells, which are important for the immunosurveillance of cancer. Glutor treatment effectively inhibits glycolysis in NK cells. However, acute treatment with the inhibitor has no effect on NK cell effector functions. Prolonged inhibition of glucose uptake by Glutor prevents the proliferation of NK cells, increases their pro-inflammatory regulatory function and reduces the stimulation-dependent production of IFN-γ. Interestingly, even after prolonged Glutor treatment NK cell cytotoxicity and serial killing activity were still intact, demonstrating that cytotoxic NK cell effector functions are remarkably robust against metabolic disturbances. Full article

Background: Despite recent advances and refinements in perioperative management of kidney transplantation (KT), early renal graft injury (eRGI) remains a critical problem with serious impairment of graft function as well as short- and long-term outcome. Serial monitoring of peripheral blood innate immune cells might be a useful tool in predicting post-transplant eRGI and graft outcome after KT. Methods: In this prospective study, medical data of 50 consecutive patients undergoing KT at the University Hospital of Leipzig were analyzed starting at the day of KT until day 10 after the transplantation. The main outcome parameter was the occurrence of eRGI and other outcome parameters associated with graft function/outcome. eRGI was defined as graft-related complications and clinical signs of renal IRI (ischemia reperfusion injury), such as acute tubular necrosis (ATN), delayed graft function (DGF), initial nonfunction (INF) and graft rejection within 3 months following KT. Typical innate immune cells including neutrophils, natural killer (NK) cells, monocytes, basophils and dendritic cells (myeloid, plasmacytoid) were measured in all patients in peripheral blood at day 0, 1, 3, 7 and 10 after the transplantation. Receiver operating characteristics (ROC) curves were performed to assess their predictive value for eRGI. Cutoff levels were calculated with the Youden index. Significant diagnostic immunological cutoffs and other prognostic clinical factors were tested in a multivariate logistic regression model. Results: Of the 50 included patients, 23 patients developed eRGI. Mean levels of neutrophils and monocytes were significantly higher on most days in the eRGI group compared to the non-eRGI group after transplantation, whereas a significant decrease in NK cell count, basophil levels and DC counts could be found between baseline and postoperative course. ROC analysis indicated that monocytes levels on POD 7 (AUC: 0.91) and NK cell levels on POD 7 (AUC: 0.92) were highly predictive for eRGI after KT. Multivariable analysis identified recipient age (OR 1.53 (95% CI: 1.003–2.350), p = 0.040), recipient body mass index > 25 kg/m² (OR 5.6 (95% CI: 1.36–23.9), p = 0.015), recipient cardiovascular disease (OR 8.17 (95% CI: 1.28–52.16), p = 0.026), donor age (OR 1.068 (95% CI: 1.011–1.128), p = 0.027), <0.010), deceased-donor transplantation (OR 2.18 (95% CI: 1.091–4.112), p = 0.027) and cold ischemia time (CIT) of the renal graft (OR 1.005 (95% CI: 1.001–1.01), p = 0.019) as clinically relevant prognostic factors associated with increased eRGI following KT. Further, neutrophils > 9.4 × 10³/μL on POD 7 (OR 16.1 (95% CI: 1.31–195.6), p = 0.031), monocytes > 1150 cells/ul on POD 7 (OR 7.81 (95% CI: 1.97–63.18), p = 0.048), NK cells < 125 cells/μL on POD 3 (OR 6.97 (95% CI: 3.81–12.7), p < 0.01), basophils < 18.1 cells/μL on POD 10 (OR 3.45 (95% CI: 1.37–12.3), p = 0.02) and mDC < 4.7 cells/μL on POD 7 (OR 11.68 (95% CI: 1.85–73.4), p < 0.01) were revealed as independent biochemical predictive variables for eRGI after KT. Conclusions: We show that the combined measurement of immunological innate variables (NK cells and monocytes on POD 7) and specific clinical factors such as prolonged CIT, increased donor and recipient age and morbidity together with deceased-donor transplantation were significant and specific predictors of eRGI following KT. We suggest that intensified monitoring of these parameters might be a helpful clinical tool in identifying patients at a higher risk of postoperative complication after KT and may therefore help to detect and—by diligent clinical management—even prevent deteriorated outcome due to IRI and eRGI after KT. Full article

We study statistical aspects of the case of the British nurse Ben Geen, convicted of 2 counts of murder and 15 of grievous bodily harm following events at Horton General Hospital (in the town of Banbury, Oxfordshire, UK) during December 2013–February 2014. We draw attention to parallels with the cases of nurses Lucia de Berk (the Netherlands) and Daniela Poggiali (Italy), in both of which an initial conviction for multiple murders of patients was overturned after the reopening of the case. We pay most attention to the investigative processes by which data, and not just statistical data, is generated; namely, the identification of past cases in which the nurse under suspicion might have been involved. We argue that the investigation and prosecution of such cases are vulnerable to many cognitive biases and errors of reasoning about uncertainty, exacerbated by the fact that fact-finders have to determine not only whether a particular person was guilty of certain crimes, but whether any crimes were committed by anybody at all. The paper includes some new statistical findings on the Ben Geen case and suggests further avenues for investigation. The experiences recounted here have contributed to the writing of the handbook Healthcare Serial Killer or Coincidence? Statistical Issues in Investigation of Suspected Medical Misconduct, Royal Statistical Society, London, 2022. Full article

We have come to a point where the field of fan studies must acknowledge darker, more pathologized and potentially more sinister forms of fandom than we have heretofore. Serial killer fandom is, simultaneously, one of the most visible and least-academically discussed form of fandom, despite a general recognition that certain serial killers are, undeniably, celebrities. Serial killer fanfic is relatively rare, but it certainly exists. In this article, I build on some of the work I have already done on Real Person Fiction, specifically importing the lenses of metalepsis and multimodality as well as the self-conscious intersection between fiction and reality, to look at an example of serial killer fanfic on three platforms—Ao3, Tumblr and Wattpad. The article asks what we can learn from applying a fan studies approach to this phenomenon. Is there anything uniquely problematic about serial killer fanfiction, or is it the same process as what so many already do as a mainstream cultural practice, hypothesizing and imagining the ‘backstage’ of famous serial killers, as we do with all other celebrities? I compare the 2019 film Extremely Wicked, Shockingly Evil and Vile which focuses on Bundy’s private relationship with his long-time girlfriend, his circus-like televised murder trial and his eventual death sentence, with a selection of Ted Bundy fanfiction. Of course, the film does not call itself fanfiction (though several critics have considered it to glorify its subject). I will argue that the distinction between ‘serial killer fanfiction’ and authorized, industrialized and popular forms of serial killer media, actually, has very little to do with the content of the text, and is based on a complex network of assumptions regarding its author, context and modes of production and reception. If this is so, the questions we should ask of serial killer fanfic are, in fact, much broader questions regarding our cultural fascination with serial killer media, challenging the pathologization of a specific, feminine-coded and extremely stigmatized fannish practice. Full article

Serial murder is a specific type of violent crime that falls into the crime category of multicide. According to the nomenclature of the Federal Bureau of Investigation’s Violent Crime Classification Manual and Academic Researchers for the Classification of Violent Crimes, most serial killers are adults. However, serial murder is also committed by young people, although to a lesser extent. Young serial killers are a topic of relevance in areas such as psychology, criminology, and the justice system. Given that the study of the variables that could be the basis of such multicide criminality is not conclusive, the need for further research is evident. The homicides perpetrated by children and young people point to a social panorama that is alarming due to their young age. This issue is prevalent enough to conduct a review. The performed review concludes the importance of psychosocial factors to better understand the process by which children and young people commit crimes as serious as serial murders. The scope of the problem of serial murders perpetrated by minors is controversial because it often depends on how the number of real cases is counted. Although official statistics indicate the low prevalence of juvenile serial killers, childhood is a period in which antisocial behaviour can have its beginning. Some authors consider that it is not uncommon for the first murder of this type to occur in adolescence. It is important to consider psychopathy as an influential factor in the various forms of serial criminal conduct committed by children and young people. The research works consulted provide evidence of the special relevance of psychopathy in the generation of serious juvenile delinquency. Full article

Sharks are among the most endangered nonhuman animals on the planet because of industrial fishing, the shark meat and fin trade, expanding recreational fishing, and other anthropogenic causes. White sharks (Carcharodon carcharias), the most visible in popular culture, remain vulnerable (VU, IUCN Red List) and understudied, although population recovery is having a measure of success in regions like the Eastern Pacific and the Northern Atlantic of the United States. As numbers rise, Jaws associations also remain in vogue in programming that emphasizes human–wildlife** conflict such as Shark Week’s Great White Serial Killer Lives. Network marketing typically promotes this content by hyping shark science. Textual analysis, however, suggests that exposure to pseudoscientific narratives and unethical fear-inducing images is counterproductive to wider support for conservation programs and public recognition for sharks’ rights to their habitats. Full article

The prognosis of multiple myeloma (MM) has drastically improved owing to the development of new drugs, such as proteasome inhibitors and immunomodulatory drugs. Nevertheless, MM is an extremely challenging disease, and many patients are still refractory to the existing therapies, thus requiring new treatment alternatives. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 that shows efficacy in MM not only as a single agent but also in combination therapy, especially for MM patients with translocation t(11;14). However, many patients are refractory to this drug. Here, we treated the MM cell lines KMS12PE and KMS27 with a combination treatment of venetoclax targeting BCL-2 and daratumumab targeting CD38 to evaluate the synergistic cytotoxicity of these drugs in vitro. MM cell lines were co-cultured with natural killer (NK) cells at an effector:target ratio of 0.3:1 in the presence of serial concentrations of daratumumab and venetoclax, and the resulting apoptotic MM cells were detected by flow cytometry using annexin V. These results indicated that the antibody-dependent cell-mediated NK cytotoxicity was enhanced in KMS12PE and KMS27 cells harboring t(11;14) with a high BCL-2 expression, suggesting that the combination treatment of venetoclax and daratumumab should be especially effective in patients with these characteristics. Full article

NK cell ADCC supports monoclonal antibody anti-tumor therapies. We investigated serial ADCC and whether it could be predicted by NK phenotypes, including expression of CD16A, CD2 and perforin. CD16A, the NK receptor for antibodies, has AA158 valine or phenylalanine variants with different affinities for IgG. CD2, a costimulatory protein, associates with CD16A and can augment CD16A-signaling. Pore-forming perforin is essential for rapid NK-mediated killing. NK cells were monitored for their ADCC serial killing frequency (KF). KF is the average number of target cells killed per cell by a cytotoxic cell population. KF comparisons were made at 1:4 CD16pos NK effector:target ratios. ADCC was toward Daudi cells labeled with ⁵¹Cr and obinutuzumab anti-CD20 antibody. CD16A genotypes were determined by DNA sequencing. CD2, CD16A, and perforin expression was monitored by flow cytometry. Serial killing KFs varied two-fold among 24 donors and were independent of CD16A genotypes and perforin levels. However, high percentages of CD2pos of the CD16Apos NK cells and high levels of CD16A were associated with high KFs. ROC analysis indicated that the %CD2pos of CD16Apos NK cells can predict KFs. In conclusion, the extent of serial ADCC varies significantly among donors and appears predictable by the CD2posCD16Apos NK phenotype. Full article

This exploratory study analyzed how three serial killers (i.e., Bundy, Gacy, and Dahmer) potentially rationalized and justified their murders by applying techniques of neutralization. This paper discusses how the use of these neutralizations also functions as a form of stigma management assisting in the maintenance of a positive presentation of self, thus mitigating responsibility for their crimes. This study conducted a content analysis of data comprised from interviews and case histories of these three serial killers. Based on these analyses, the impression is conveyed that these killers used neutralizations to manage their identities (i.e., present “normal” selves), mitigate responsibility for their actions, and minimize the stigma associated with being labeled a serial killer. Full article

Patients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy is an attractive and novel option, which has shown encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. However, the underlying mechanisms of, and approaches to overcome, acquired anti-CD19CAR CD8⁺ T cells (CTL)-resistance in NHL remain elusive. CD19CAR transduced primary human CTLs kill CD19⁺ human NHLs in a CD19- and caspase-dependent manner, mainly via the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) apoptotic pathway. To understand the dynamics of the development of resistance, we analyzed several anti-CD19CAR CTL-resistant NHL sublines (R-NHL) derived by serial exposure of sensitive parental lines to excessive numbers of anti-CD19CAR CTLs followed by a limiting dilution analysis. The R-NHLs retained surface CD19 expression and were efficiently recognized by CD19CAR CTLs. However, R-NHLs developed cross-resistance to CD19CAR transduced human primary CTLs and the Jurkat human T cell line, activated Jurkat, and lymphokine activated killer (LAK) cells, suggesting the acquisition of resistance is independent of CD19-loss and might be due to aberrant apoptotic machinery. We hypothesize that the R-NHL refractoriness to CD19CAR CTL killing could be partially rescued by small molecule sensitizers with apoptotic-gene regulatory effects. Chromatin modifiers and Celecoxib partially reversed the resistance of R-NHL cells to the cytotoxic effects of anti-CD19CAR CTLs and rhTRAIL. These in vitro results, though they require further examination, may provide a rational biological basis for combination treatment in the management of CD19CAR CTL-based therapy of NHL. Full article