Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor with early dissemination and dismal prognosis, accounts for 15-20% of lung cancer cases and ∼200,000 deaths each year. Most cases are ...inoperable, and biopsies to investigate SCLC biology are rarely obtainable. Circulating tumor cells (CTCs), which are prevalent in SCLC, present a readily accessible 'liquid biopsy'. Here we show that CTCs from patients with either chemosensitive or chemorefractory SCLC are tumorigenic in immune-compromised mice, and the resultant CTC-derived explants (CDXs) mirror the donor patient's response to platinum and etoposide chemotherapy. Genomic analysis of isolated CTCs revealed considerable similarity to the corresponding CDX. Most marked differences were observed between CDXs from patients with different clinical outcomes. These data demonstrate that CTC molecular analysis via serial blood sampling could facilitate delivery of personalized medicine for SCLC. CDXs are readily passaged, and these unique mouse models provide tractable systems for therapy testing and understanding drug resistance mechanisms.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A safe, effective, and scalable vaccine is needed to halt the ongoing SARS-CoV-2 pandemic. We describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent ...and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 SARS-CoV-2 spike receptor-binding domains (RBDs) in a highly immunogenic array and induce neutralizing antibody titers 10-fold higher than the prefusion-stabilized spike despite a 5-fold lower dose. Antibodies elicited by the RBD nanoparticles target multiple distinct epitopes, suggesting they may not be easily susceptible to escape mutations, and exhibit a lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the assembled nanoparticles suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms and have launched cGMP manufacturing efforts to advance the SARS-CoV-2-RBD nanoparticle vaccine into the clinic.
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•Two-component nanoparticle platform enabled rapid generation of SARS-CoV-2 vaccines•The RBD-nanoparticle vaccines elicit potent neutralizing antibody responses•Nanoparticle vaccine-elicited antibodies target multiple non-overlapping epitopes•The lead nanoparticle vaccine candidate is being manufactured for clinical trials
Walls et al. describe a potential nanoparticle vaccine for COVID-19, made of a self-assembling protein nanoparticle displaying the SARS-CoV-2 receptor-binding domain in a highly immunogenic array reminiscent of the natural virus. Their nanoparticle vaccine candidate elicits a diverse, potent, and protective antibody response, including neutralizing antibody titers 10-fold higher than the prefusion-stabilized spike ectodomain trimer.
Abstract
Romance fraud affects thousands of victims globally, yet few scholars have studied it. The dynamics of relationships between victims and offenders are not well understood, and the effects ...are rarely discussed. This article adapts the concept of psychological abuse from studies of domestic violence to better understand romance fraud. Using interviews with 21 Australian romance fraud victims, we show how offenders use non-violent tactics to ensure compliance with ongoing demands for money. This article identifies similarities and differences between domestic violence and romance fraud. We argue that thinking through domestic violence and romance fraud together offers potential benefits to both bodies of research.
Coatomer complex I (COPI) mediates retrograde vesicular trafficking from Golgi to the endoplasmic reticulum (ER) and within Golgi compartments. Deficiency in subunit alpha causes COPA syndrome and is ...associated with type I IFN signalling, although the upstream innate immune sensor involved was unknown. Using in vitro models we find aberrant activation of the STING pathway due to deficient retrograde but probably not intra-Golgi transport. Further we find the upstream cytosolic DNA sensor cGAS as essentially required to drive type I IFN signalling. Genetic deletion of COPI subunits COPG1 or COPD similarly induces type I IFN activation in vitro, which suggests that inflammatory diseases associated with mutations in other COPI subunit genes may exist. Finally, we demonstrate that inflammation in COPA syndrome patient peripheral blood mononuclear cells and COPI-deficient cell lines is ameliorated by treatment with the small molecule STING inhibitor H-151, suggesting targeted inhibition of the cGAS/STING pathway as a promising therapeutic approach.
The monocarboxylate transporter 1 (MCT1) inhibitor, AZD3965, is undergoing phase I evaluation in the United Kingdom. AZD3965 is proposed, via lactate transport modulation, to kill tumor cells reliant ...on glycolysis. We investigated the therapeutic potential of AZD3965 in small cell lung cancer (SCLC) seeking rationale for clinical testing in this disease and putative predictive biomarkers for trial use.
AZD3965 sensitivity was determined for seven SCLC cell lines, in normoxia and hypoxia, and for a tumor xenograft model. Proof of mechanism was sought via changes in intracellular/tumor lactate. Expression of MCT1 and related transporter MCT4 was assessed by Western blot analysis. Drug resistance was investigated via MCT4 siRNAi and overexpression. The expression and clinical significance of MCT1 and MCT4 were explored in a tissue microarray (TMA) from 78 patients with SCLC.
AZD3965 sensitivity varied in vitro and was highest in hypoxia. Resistance in hypoxia was associated with increased MCT4 expression. In vivo, AZD3965 reduced tumor growth and increased intratumor lactate. In the TMA, high MCT1 expression was associated with worse prognosis (P = 0.014). MCT1 and hypoxia marker CA IX expression in the absence of MCT4 was observed in 21% of SCLC tumors.
This study provides a rationale to test AZD3965 in patients with SCLC. Our results suggest that patients with tumors expressing MCT1 and lacking in MCT4 are most likely to respond.
New-generation transdermal monitors such as the ION Research Alpha Prototypes (ION RAP) hold promise for real-time alcohol measurement, with improvements in design features such as sampling ...frequency, size, and comfort. This paper aims to provide the first comparisons of the wrist-worn enzyme-based ION RAP and the fuel cell-based SCRAM-CAM against breath alcohol concentration (BrAC) readings.
Participants (N = 23) completed a total of 69 laboratory alcohol administration sessions while wearing both a prototype of the ION RAP wristband and a SCRAM-CAM ankle monitor; they also gave breath samples each 10 min. Analyses focused on latencies of transdermal alcohol concentration (TAC) after alcohol ingestion, correlations, and cross-correlations between BrAC and TAC measurements.
A high failure rate of the ION RAP was observed (61.5% of the sessions were excluded due to the sessions not containing enough valid data). On average, the SCRAM-CAM and ION RAP detected alcohol 43 (SD = 21) and 50 (SD = 27) minutes after the first drink, with peak values reached after 138 (SD = 47) and 154 (SD = 56) minutes, respectively. SCRAM-CAM TAC peak (r = 0.185, p = 0.375) and area under the curve (AUC; r = 0.320, p = 0.118) showed small- and medium-sized correlations to BrAC. ION RAP TAC peak (r = −0.082, p = 0.698) and AUC (r = 0.040, p = 0.852) correlations to BrAC were close to zero.
In this study, the new-generation ION RAP and the traditionally used SCRAM-CAM show similar delays in detection and similar TAC curves over time, despite using either enzyme- or fuel cell-based technologies, respectively. Due to high failure rates of the ION RAP prototypes and close to zero correlations to BrAC, further developments and improvements of these TAC wristbands are required for reliable and valid use in real-time alcohol measurement.
•The transdermal alcohol monitors ION RAP and SCRAM-CAM were evaluated against breath alcohol concentration.•The failure rate for the ION RAP wristband was 62% and 0% for the SCRAM-CAM.•The enzyme-based ION RAP and fuel-cell SCRAM-CAM had similar alcohol detection delays.•BrAC correlations were higher for SCRAM-CAM (r = 0.19–0.32) than for ION RAP (r = −0.09–0.04).•Maximal cross-correlation coefficients ranged from 0.63 to 0.67.
The origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing the global coronavirus disease 19 (COVID-19) pandemic, remains a mystery. Current evidence suggests a ...likely spillover into humans from an animal reservoir. Understanding the host range and identifying animal species that are susceptible to SARS-CoV-2 infection may help to elucidate the origin of the virus and the mechanisms underlying cross-species transmission to humans. Here we demonstrated that white-tailed deer (
), an animal species in which the angiotensin converting enzyme 2 (ACE2) - the SARS-CoV-2 receptor - shares a high degree of similarity to humans, are highly susceptible to infection. Intranasal inoculation of deer fawns with SARS-CoV-2 resulted in established subclinical viral infection and shedding of infectious virus in nasal secretions. Notably, infected animals transmitted the virus to non-inoculated contact deer. Viral RNA was detected in multiple tissues 21 days post-inoculation (pi). All inoculated and indirect contact animals seroconverted and developed neutralizing antibodies as early as day 7 pi. The work provides important insights into the animal host range of SARS-CoV-2 and identifies white-tailed deer as a susceptible wild animal species to the virus.
Given the presumed zoonotic origin of SARS-CoV-2, the human-animal-environment interface of COVID-19 pandemic is an area of great scientific and public- and animal-health interest. Identification of animal species that are susceptible to infection by SARS-CoV-2 may help to elucidate the potential origin of the virus, identify potential reservoirs or intermediate hosts, and define the mechanisms underlying cross-species transmission to humans. Additionally, it may also provide information and help to prevent potential reverse zoonosis that could lead to the establishment of a new wildlife hosts. Our data show that upon intranasal inoculation, white-tailed deer became subclinically infected and shed infectious SARS-CoV-2 in nasal secretions and feces. Importantly, indirect contact animals were infected and shed infectious virus, indicating efficient SARS-CoV-2 transmission from inoculated animals. These findings support the inclusion of wild cervid species in investigations conducted to assess potential reservoirs or sources of SARS-CoV-2 of infection.
We used social identity theory to examine predictors of antiasexual bias in a sample of 1297 adults (48.6% female, 43.2% male, 6.4% nonbinary/other, 0.6% questioning). Multiple regression analysis ...found that social dominance orientation, right wing authoritarianism, singlism, low relational closeness with asexual individuals, and sexual orientation were significant predictors of antiasexual bias. In support of social identity theory, and consistent with existing research on antiasexual bias, non-LGBTQ+ participants ( n = 576) scored higher on measures of antiasexual attitudes compared to nonasexual LGBTQ+ ( n = 569) and asexual individuals ( n = 143). Shared status as sexual minorities appears to provide common ground between asexuality and other LGBTQ+ identities.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
A quick, simple, and high‐yield nucleic acid isolation process is crucial for high‐quality DNA analysis. The ability of the MicroGEM PDQeX phytoGEM system and Omega Bio‐tek E.Z.N.A.® Plant DS Mini ...kit to extract PCR‐ready DNA was evaluated by extracting the forensically relevant “legal high” plant species: Ipomoea purpurea, Artemisia absinthium, Mitragyna speciosa, Datura stramonium, and Papaver somniferum. The plant material was pulverized, processed using the manufacturer’s plant protocol for the PDQeX Nucleic Acid Extraction or the manufacturer’s protocol for the Omega extraction, quantified using the Invitrogen Qubit 2.0 Fluorometer, and analyzed for amplifiability by PCR using a Qiagen Rotor‐Gene Q instrument and published assays. The DNA amplicons for the legal high species produced high‐resolution melt curves concordant with the melts observed when DNA was isolated using the Qiagen DNeasy Plant Mini Kit in previous studies.
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