When a person openly “regrets” their gender transition or “detransitions” this bolsters within the medical community an impression that transgender and non-binary (trans) people require close ...scrutiny when seeking hormonal and surgical interventions. Despite the low prevalence of “regretful” patient experiences, and scant empirical research on “detransition”, these rare transition outcomes profoundly organize the gender-affirming medical care enterprise. Informed by the tenets of institutional ethnography, we examined routine gender-affirming care clinical assessment practices in Canada. Between 2017 and 2018, we interviewed 11 clinicians, 2 administrators, and 9 trans patients (total n = 22), and reviewed 14 healthcare documents pertinent to gender-affirming care in Canada. Through our analysis, we uncovered pervasive regret prevention techniques, including requirements that trans patients undergo extensive psychosocial evaluations prior to transitioning. Clinicians leveraged psychiatric diagnoses as a proxy to predict transition regret, and in some cases delayed or denied medical treatments. We identified cases of patient dissatisfaction with surgical results, and a person who detransitioned. These accounts decouple transition regret and detransition, and no participants endorsed stricter clinical assessments. We traced the clinical work of preventing regret to cisnormativity and transnormativity in medicine which together construct regret as “life-ending”, and in turn drives clinicians to apply strategies to mitigate the perceived risk of malpractice legal action when treating trans people, specifically. Yet, attempts to prevent these outcomes contrast with the material healthcare needs of trans people. We conclude that regret and detransitioning are unpredictable and unavoidable clinical phenomena, rarely appearing in “life-ending” forms. Critical research into the experiences of people who detransition is necessary to bolster comprehensive gender-affirming care that recognizes dynamic transition trajectories, and which can address clinicians’ fears of legal action—cisgender anxieties projected onto trans patients who are seeking medical care.
•Gender-affirming medical care is built around preventing transition “regret”.•Clinical assessments reflect clinicians' fears of liability.•There is scant evidence that detransition is caused by medical failure.•Include trans and detransitioned people in gender-affirming care research.
The rescue effect describes the phenomenon where irradiated cells or organisms derive benefits from the feedback signals sent from the bystander unirradiated cells or organisms. An example of the ...benefit is the mitigation of radiation-induced DNA damages in the irradiated cells. The rescue effect can compromise the efficacy of radioimmunotherapy (RIT) (and actually all radiotherapy). In this paper, the discovery and subsequent confirmation studies on the rescue effect were reviewed. The mechanisms and the chemical messengers responsible for the rescue effect studied to date were summarized. The rescue effect between irradiated and bystander unirradiated zebrafish embryos in vivo sharing the same medium was also described. In the discussion section, the mechanism proposed for the rescue effect involving activation of the nuclear factor κB (NF-κB) pathway was scrutinized. This mechanism could explain the promotion of cellular survival and correct repair of DNA damage, dependence on cyclic adenosine monophosphate (cAMP) and modulation of intracellular reactive oxygen species (ROS) level in irradiated cells. Exploitation of the NF-κB pathway to improve the effectiveness of RIT was proposed. Finally, the possibility of using zebrafish embryos as the model to study the efficacy of RIT in treating solid tumors was also discussed.
Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. Z-DNA binding protein 1 (ZBP1) activates inflammatory cell death, PANoptosis, ...whereas adenosine deaminase acting on RNA 1 (ADAR1) serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1’s interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining interferons (IFNs) and nuclear export inhibitors (NEIs) activates ZBP1-dependent PANoptosis. ADAR1 suppresses this PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1fl/flLysMcre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wild-type mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1-dependent manner. Our findings suggest that ADAR1 suppresses ZBP1-mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to informing therapeutic strategies for cancer and other diseases.
Display omitted
•Combining IFNs with NEIs induces ZBP1-mediated inflammatory cell death, PANoptosis•ADAR1 negatively regulates the ZBP1-mediated PANoptosis•Blocking ADAR1 activity unleashes ZBP1-mediated PANoptosis to inhibit tumorigenesis•In mice, IFN-γ + KPT-330 dramatically regresses tumors in a ZBP1-dependent manner
Karki et al. identify a critical role for ADAR1 in regulating ZBP1-mediated inflammatory cell death, PANoptosis. Treating with IFNs, which upregulate ADAR1 and ZBP1, and nuclear export inhibitors, which sequester ADAR1 in the nucleus, induces robust cell death that inhibits tumorigenesis in vivo, suggesting a therapeutic strategy.
Water plays an important role in power generation, fuel manufacturing, and processing. This has been valid for several decades, but lately, primarily due to climate change, the limitations and ...insecurity related to water energy connections have become more prominent. The article is a quantitative review study conducted to evaluate the water–energy nexus in the Middle East and North Africa (MENA) region. Information about the review was generated from online databases by using keywords such as water–energy nexus, MENA region, Power Generation, Fuel Manufacturing, Energy-intensive, Energy Management Decisions, and Desalination Systems. Drip irrigation in Morocco played a vital role in the water–energy nexus for resource conservation and their better utilization. From the findings, it was revealed that distorted coupling with a relatively low reliance on freshwater energy systems has a high reliance on conceptual water and energy production systems. For Saudi Arabia, extraction and desalination of groundwater are projected to be up to 9% of total annual electricity use. Policymakers should consider energy implications for water-intensive food imports and possible water demand restructuring. This would lead to more coordinated water and energy management decisions. A comprehensive evaluation in some cases promotes the reuse of water and improvements in the agricultural sector rather than the development of energy-intensive and expensive desalination systems. One of the limitations for water–energy nexus in the MENA region is its unintelligible patterns for policy and decision-makers, and this quantitative review can be a major advancement in this regard. This study also highlights the use of water as an energy production source as well as the energy that is being utilized in water treatment and processing and their interrelationship. Cohesive and strategic tactics can lead technology’s research and development to reporting local issues of water and energy issues. Improving and participating models and data will better assist scholars, decision-makers, and the community. This water–energy nexus study mounts relevant challenges and areas of improvement for future research.
Nonlinear optical processes at soft x-ray wavelengths have remained largely unexplored due to the lack of available light sources with the requisite intensity and coherence. Here we report the ...observation of soft x-ray second harmonic generation near the carbon K edge (∼284 eV) in graphite thin films generated by high intensity, coherent soft x-ray pulses at the FERMI free electron laser. Our experimental results and accompanying first-principles theoretical analysis highlight the effect of resonant enhancement above the carbon K edge and show the technique to be interfacially sensitive in a centrosymmetric sample with second harmonic intensity arising primarily from the first atomic layer at the open surface. This technique and the associated theoretical framework demonstrate the ability to selectively probe interfaces, including those that are buried, with elemental specificity, providing a new tool for a range of scientific problems.
Previous studies from our group and others have shown that cyclooxygenase-2 (COX-2) has an essential role in radiation-induced non-targeted responses and genomic instability in vivo. However, the ...signalling pathways involved in such effects remain unclear.
A 1 cm(2) area (1 cm × 1 cm) in the lower abdominal region of gpt delta transgenic mice was irradiated with 5 Gy of 300 keV X-rays. Nimesulide, a selective COX-2 inhibitor, was given to mice for five consecutive days before irradiation. Changes in transforming growth factor-beta (TGF-β) and TGF-β receptor type-1 (TGFBR1) mediated signalling pathways, in the out of radiation field lung and liver tissues were examined.
While the plasma level of cytokines remained unchanged, the expression of TGF-β and its receptors was elevated in non-targeted lung tissues after partial body irradiation. In contrast to the predominant expression of TGF-β in stromal and alveolar cells, but not in bronchial epithelial cells, TGF-β receptors, especially TGFBR1 were significantly elevated in non-targeted bronchial epithelial cells, which is consistent with the induction of COX-2. The different expression levels of TGFBR1 between liver and lung resulted in a tissue specific induction of COX-2 in these two non-targeted tissues. Multiple TGF-β induced signalling pathways were activated in the non-targeted lung tissues.
The TGFβ-TGFBR1-COX-2 Signalling Pathway has a critical role in radiation-induced non-targeted response in vivo.
Lack of access to healthcare services for people living in the Circumpolar North may have important consequences for their health and well-being, both in terms of the actual treatment and other ...possible health-related consequences intertwined with their life situation. The aim of the present study was to identify the specific challenges to healthcare service delivery and access for populations in the Circumpolar North that are addressed in contemporary literature. A scoping review of literature published between 2005 and 2016 was conducted and 43 articles were selected for inclusion into the review. The review findings address 4 main themes identified in the literature: (1) the influence of physical geography, (2) healthcare provider-related barriers, (3) the importance of culture and language and (4) the impact of systemic factors. The review of the literature enabled us to identify existing gaps in both health service access and issues discussed in the available literature, particularly for informing healthcare services in the Circumpolar North, as well as point towards opportunities for future research. The thematic findings drawn from interdisciplinary and international literature inform understandings of the impact of health system barriers on healthcare services and the opportunities for Northern residents to support their own health.
Inteins, also known as “protein introns,” have been found to be present in many microbial species and widely employed for the expression and purification of recombinant proteins in
Escherichia coli
. ...However, interestingly, until now there has not been much information on the identification and application of inteins to protein expression in
Bacillus subtilis
. In this article, for the first time, despite the likelihood of absence of inteins in
B. subtilis
, this bacterium was shown to be able to facilitate auto-catalytic cleavages of fusions formed between inteins and recombinant proteins. Employing a construct expressing the intein,
Ssp
DnaB, (DnaB), which was fused at its N-terminus with the cellulose-binding domain (CellBD) of an endoglucanase encoded by the
cenA
gene of
Cellulomonas fimi
, the construct was demonstrated to be capable of mediating intracellular expression of basic fibroblast growth factor (bFGF), followed by auto-processing of the CellBD-DnaB-bFGF fusion to result in bFGF possessing the 146-residue authentic structure. The mentioned fusion was shown to result in a high yield of 84 mg l
−1
of biologically active bFGF. Future work in improving the growth of
B. subtilis
may enable the use of this bacterium, working in cooperation with inteins, to result in a new platform for efficient expression of valuable proteins.
A rapid microarray assay, Nanosphere Verigene® Gram-negative blood culture test (BC-GN), detects four Gram-negative species, four Gram-negative genera, and six resistance genes directly from positive ...blood culture samples, shortening the time from Gram stain to pathogen and resistance-gene identification. The purpose of this study was to determine the impact of the BC-GN paired with an antimicrobial stewardship intervention on antimicrobial and clinical outcomes. Patients with Gram-negative bacteremia were compared before (
n
= 456) and after (
n
= 421) BC-GN implementation. The primary objective was to compare time from Gram stain to antimicrobial switch pre- and post-implementation. Time from Gram stain to effective treatment, in-hospital mortality, and hospital length of stay were also compared. The number and type of antimicrobial switches were similar between groups. Median (IQR) time from Gram stain to antimicrobial switch was significantly decreased in the post group, 28.6 (8.6–56.9) h vs 44.1 (18.9–64.6) h,
p
= 0.004. In patients on ineffective antimicrobial therapy at the time of result, median time to effective therapy was lower in the post group, 8.8 (5.5–18.4) h vs 24.5 (4.9–44.3) h,
p
= 0.034. Median (IQR) hospital length of stay was also decreased in the post group, 7 (5–15) days vs 9 (4.5–21) days,
p
= 0.001. The rate of in-hospital mortality was similar between groups, 11.6% (pre) vs 11.4% (post),
p
= 0.87. Rapid microarray testing on blood cultures combined with active antimicrobial stewardship intervention was associated with decreased time to antimicrobial switch, time to effective therapy, and hospital length of stay.
Brain metastasis (BRM) is uncommon in gastroesophageal cancer. As such, clinicopathologic and molecular determinants of BRM and impact on clinical outcome remain incompletely understood.
We ...retrospectively analyzed clinicopathologic data from advanced esophageal/gastroesophageal junction (E/GEJ) patients at Johns Hopkins from 2003 to 2021. We investigated the association between several clinical and molecular features and the occurrence of BRM, with particular focus on human epidermal growth factor receptor 2 (HER2) overexpression. Survival outcomes and time to BRM onset were also evaluated.
We included 515 patients with advanced E/GEJ cancer. Tumors were 78.3% esophageal primary, 82.9% adenocarcinoma, 31.0% HER2 positive. Cumulative incidence of BRM in the overall cohort and within HER2+ subgroup was 13.8% and 24.3%, respectively. HER2 overexpression was associated with increased risk of BRM odds ratio 2.45; 95% confidence interval (CI) 1.10-5.46. On initial presentation with BRM, 50.7% had a solitary brain lesion and 11.3% were asymptomatic. HER2+ status was associated with longer median time to onset of BRM (14.0 versus 6.3 months, P < 0.01), improved median progression free survival on first-line systemic therapy (hazard ratio 0.35, 95% CI 0.16-0.80), and improved median overall survival (hazard ratio 0.20, 95% CI 0.08-0.54) in patients with BRM.
HER2 overexpression identifies a gastroesophageal cancer molecular subtype that is significantly associated with increased risk of BRM, though with later onset of BRM and improved survival likely reflecting the impact of central nervous system-penetrant HER2-directed therapy. The prevalence of asymptomatic and solitary brain lesions suggests that brain surveillance for HER2+ patients warrants prospective investigation.
PDF
