Taurine deficiency as a driver of aging Singh, Parminder; Gollapalli, Kishore; Mangiola, Stefano ...
Science (American Association for the Advancement of Science),
06/2023, Volume:
380, Issue:
6649
Journal Article
Peer reviewed
Open access
Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, ...and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.
IMPORTANCE: Policies and practices that promote advance care planning and advance directive completion implicitly assume that patients’ choices for end-of-life (EOL) care are stable over time, even ...with changes in health status. OBJECTIVE: To systematically evaluate the evidence on the stability of EOL preferences over time and with changes in health status. EVIDENCE REVIEW: We searched for longitudinal studies of patients’ preferences for EOL care in PubMed, EMBASE, and using citation review. Studies restricted to preferences regarding the place of care at the EOL were excluded. FINDINGS: A total of 296 articles were assessed for eligibility, and 59 met inclusion criteria. Twenty-four articles had sufficient data to extract or calculate the percentage of individuals with stable preferences or the percentage of total preferences that were stable over time. In 17 studies (71%) more than 70% of patients’ preferences for EOL care were stable over time. Preference stability was generally greater among inpatients and seriously ill outpatients than among older adults without serious illnesses (P < .002). Patients with higher education and who had engaged in advance care planning had greater preference stability, and preferences to forgo therapies were generally more stable than preferences to receive therapies. Among 9 of the 24 studies (38%) assessing changes in health status, no consistent relationship with preference changes was identified. CONCLUSIONS AND RELEVANCE: Considerable variability among studies in the methods of preference assessment, the time between assessments, and the definitions of stability preclude meta-analytic estimates of the stability of patients’ preferences and the factors influencing these preferences. Although more seriously ill patients and those who engage in advance care planning most commonly have stable preferences for future treatments, further research in real-world settings is needed to confirm the utility of advance care plans for future decision making.
Despite continued growth in enrollments, graduate program attrition rates are of great concern to academic program coordinators. It is estimated that only 40 to 50 percent of students who begin Ph.D. ...programs complete their degrees. This book describes programs, initiatives, and interventions that lead to overall student retention and success.Written for graduate school administrators, student affairs professionals, and faculty, this book offers ways to better support today's graduate student population, addresses the needs of today's changing student demography and considers the challenges today's graduate students face inside and outside of the classroom. The opening section highlights the shifting demographics and contextual factors shaping graduate education over the past 20 years, while the second describes institutional practices to develop the requisite academic and professional development necessary to succeed in master's and doctoral programs. In conclusion, the editors curate a conversation about different ways institutions can support graduate students beyond the classroom.
Duchenne muscular dystrophy (DMD) is characterized by rapid wasting of skeletal muscle. Mitochondrial dysfunction is a well-known pathological feature of DMD. However, whether mitochondrial ...dysfunction occurs before muscle fiber damage in DMD pathology is not well known. Furthermore, the impact upon heterozygous female
carriers (
/+), who display dystrophin mosaicism, has received little attention. We hypothesized that dystrophin deletion leads to mitochondrial dysfunction, and that this may occur before myofiber necrosis. As a secondary complication to mitochondrial dysfunction, we also hypothesized metabolic abnormalities prior to the onset of muscle damage. In this study, we detected aberrant mitochondrial morphology, reduced cristae number, and large mitochondrial vacuoles from both male and female
mice prior to the onset of muscle damage. Furthermore, we systematically characterized mitochondria during disease progression starting before the onset of muscle damage, noting additional changes in mitochondrial DNA copy number and regulators of mitochondrial size. We further detected mild metabolic and mitochondrial impairments in female
carrier mice that were exacerbated with high-fat diet feeding. Lastly, inhibition of the strong autophagic program observed in adolescent
male mice via administration of the autophagy inhibitor leupeptin did not improve skeletal muscle pathology. These results are in line with previous data and suggest that before the onset of myofiber necrosis, mitochondrial and metabolic abnormalities are present within the
mouse.
In the digital age, the preservation of digital cultural heritage faces unforeseen vulnerabilities during conflicts. This article dismantles the illusion of invulnerability in digital repositories ...and digital archives, revealing their susceptibility to warfare through historical examples and contemporary challenges. The Second World War serves as an example of physical assault on cultural heritage, prompting concerns about potential digital cultural genocide. The recent digital attacks on St. Louis Public Library and France’s TV5MONDE serve as examples of malicious assaults on digital cultural heritage. Information warfare, nation-state conflicts, ethnic and cultural suppression and other reasons emerge as potential threats to these digital infrastructures and resources. Beyond vulnerabilities, cybersecurity threats and digital inequality pose significant challenges. Conflict zones also face their own infrastructural challenges. Strategies for resilience are reviewed and suggestions for amendments follow, advocating for a holistic approach that integrates digital and tangible preservation methods, responsible technological advancements, community involvement and international collaboration. The article concludes by emphasizing that a nuanced and comprehensive approach to cultural heritage preservation is required during conflicts. Libraries are positioned as stewards of knowledge, advocating for the protection of our shared cultural legacy amidst fragility and times of conflict.
Background
Myelosuppression is a potential dose-limiting factor in radioligand therapy (RLT). This study aims to investigate occurrence, severity and reversibility of hematotoxic adverse events in ...patients undergoing RLT with
177
Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC). The contribution of pretreatment risk factors and cumulative treatment activity is taken into account specifically.
Methods
RLT was performed in 140 patients receiving a total of 497 cycles. A mean activity of 6.9
±
1.3 GBq
177
Lu-PSMA-617 per cycle was administered, and mean cumulative activity was 24.6
±
15.9 GBq. Hematological parameters were measured at baseline, prior to each treatment course, 2 to 4 weeks thereafter and throughout follow-up. Toxicity was graded based on Common Terminology Criteria for Adverse Events v5.0.
Results
Significant (grade ≥ 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade ≤ 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT. Myelosuppression was significantly more frequent in patients with pre-existing grade 2 cytopenia (OR: 3.50, 95%CI 1.08–11.32,
p
= 0.04) or high bone tumor burden (disseminated or diffuse based on PROMISE miTNM, OR: 5.08, 95%CI 1.08–23.86,
p
= 0.04). Previous taxane-based chemotherapy was associated with an increased incidence of significant hematotoxicity (OR: 4.62, 95%CI 1.23–17.28,
p
= 0.02), while treatment with
223
Ra-dichloride, cumulative RLT treatment activity and activity per cycle were not significantly correlated (
p
= 0.93, 0.33, 0.29).
Conclusion
Hematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous
223
Ra-dichloride treatment show no significant contribution to incidence rates.
To describe the supply of cancer specialists, the organization of cancer care within versus outside of health systems, and the distance to multispecialty cancer centers.
Using the 2018 Health Systems ...and Provider Database from the National Bureau of Economic Research and 2018 Medicare data, we identified 46,341 unique physicians providing cancer care. We stratified physicians by discipline (adult/pediatric medical oncologists, radiation oncologists, surgical/gynecologic oncologists, other surgeons performing cancer surgeries, or palliative care physicians), system type (National Cancer Institute NCI Cancer Center system, non-NCI academic system, nonacademic system, or nonsystem/independent practice), practice size, and composition (single disciplinary oncology, multidisciplinary oncology, or multispecialty). We computed the density of cancer specialists by county and calculated distances to the nearest NCI Cancer Center.
More than half of all cancer specialists (57.8%) practiced in health systems, but 55.0% of cancer-related visits occurred in independent practices. Most system-based physicians were in large practices with more than 100 physicians, while those in independent practices were in smaller practices. Practices in NCI Cancer Center systems (95.2%), non-NCI academic systems (95.0%), and nonacademic systems (94.3%) were primarily multispecialty, while fewer independent practices (44.8%) were. Cancer specialist density was sparse in many rural areas, where the median travel distance to an NCI Cancer Center was 98.7 miles. Distances to NCI Cancer Centers were shorter for individuals living in high-income areas than in low-income areas, even for individuals in suburban and urban areas.
Although many cancer specialists practiced in multispecialty health systems, many also worked in smaller-sized independent practices where most patients were treated. Access to cancer specialists and cancer centers was limited in many areas, particularly in rural and low-income areas.
Abstract
One method for reducing the impact of vector-borne diseases is through the use of CRISPR-based gene drives, which manipulate insect populations due to their ability to rapidly propagate ...desired genetic traits into a target population. However, all current gene drives employ a Cas9 nuclease that is constitutively active, impeding our control over their propagation abilities and limiting the generation of alternative gene drive arrangements. Yet, other nucleases such as the temperature sensitive Cas12a have not been explored for gene drive designs in insects. To address this, we herein present a proof-of-concept gene-drive system driven by Cas12a that can be regulated via temperature modulation. Furthermore, we combined Cas9 and Cas12a to build double gene drives capable of simultaneously spreading two independent engineered alleles. The development of Cas12a-mediated gene drives provides an innovative option for designing next-generation vector control strategies to combat disease vectors and agricultural pests.
The patient voice is becoming increasingly prominent across all stages of therapeutic innovation. It pervades research domains from funding and recruitment, to translation, care, and support. ...Advances in genomic technologies have facilitated novel breakthrough therapies, whose global developments, regulatory approvals, and confined governmental subsidisations have stimulated renewed hope amongst rare disease patient organisations (RDPOs). With intensifying optimism characterising the therapeutic landscape, researcher-advocate partnerships have reached an inflexion point, at which stakeholders may evaluate their achievements and formulate frameworks for future refinement.
Through this narrative review, we surveyed relevant literature around the roles of RDPOs catering to the rare paediatric neurological disease community. Via available literature, we considered RDPO interactions within seven domains of therapeutic development: research grant funding, industry sponsorship, study recruitment, clinical care and support, patient-reported outcome measures, and research prioritisation. In doing so, we explored practical and ethical challenges, gaps in understanding, and future directions of inquiry. Current literature highlights the increasing significance of ethical and financial challenges to patient advocacy. Biomedical venture philanthropy is gaining momentum amongst RDPOs, whose small grants can incrementally assist laboratories in research, training, and pursuits of more substantial grants. However, RDPO seed funding may encounter long-term sustainability issues and difficulties in selecting appropriate research investments. Further challenges include advocate-industry collaborations, commercial biases, and unresolved controversies regarding orphan drug subsidisation. Beyond their financial interactions, RDPOs serve instrumental roles in project promotion, participant recruitment, biobank creation, and patient registry establishment. They are communication conduits between carers, patients, and other stakeholders, but their contributions may be susceptible to bias and unrealistic expectations.
Further insights into how RDPOs navigate practical and ethical challenges in therapeutic development may enhance cooperative efforts. They may also inform resources, whose distribution among advocates, parents, and clinicians, may assist decision-making processes around rare disease clinical trials and treatments.
Full text
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Syndromes associated with LCAT deficiency, a rare autosomal recessive condition, include fish-eye disease (FED) and familial LCAT deficiency (FLD). FLD is more severe and characterized by early and ...progressive chronic kidney disease (CKD). No treatment is currently available for FLD, but novel therapeutics are under development. Furthermore, although biomarkers of LCAT deficiency have been identified, their suitability to monitor disease progression and therapeutic efficacy is unclear, as little data exist on the rate of progression of renal disease. Here, we systematically review observational studies of FLD, FED, and heterozygous subjects, which summarize available evidence on the natural history and biomarkers of LCAT deficiency, in order to guide the development of novel therapeutics. We identified 146 FLD and 53 FED patients from 219 publications, showing that both syndromes are characterized by early corneal opacity and markedly reduced HDL-C levels. Proteinuria/hematuria were the first signs of renal impairment in FLD, followed by rapid decline of renal function. Furthermore, LCAT activity toward endogenous substrates and the percentage of circulating esterified cholesterol (EC%) were the best discriminators between these two syndromes. In FLD, higher levels of total, non-HDL, and unesterified cholesterol were associated with severe CKD. We reveal a nonlinear association between LCAT activity and EC% levels, in which subnormal levels of LCAT activity were associated with normal EC%. This review provides the first step toward the identification of disease biomarkers to be used in clinical trials and suggests that restoring LCAT activity to subnormal levels may be sufficient to prevent renal disease progression.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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