The glutamate/aspartate transporter EAAT1 is crucial for T-cell acute lymphoblastic leukemia proliferation and survival.

T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we combined the analysis of T-ALL gene expression and metabolism to identify the metabolic adaptations that T-ALL cells exhibit. We found that glutamine uptake is essential for T-ALL proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the TCA cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1 (SLC1A3), which is normally expressed in the central nervous system, is crucial for glutamine conversion to aspartate and nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.

Mentoring Medical Students Towards Oncology: Results from a Pilot Multi-institutional Mentorship Programme.

The mounting global cancer burden has generated an increasing demand for oncologists to join the workforce. Yet, students report limited oncology exposure in undergraduate medical curricula, while undergraduate oncology mentorships remain underutilised. We established an undergraduate oncology society-led mentorship programme aimed at medical students across several UK universities to increase medical student oncology exposure. We electronically recruited and paired oncologist mentors and medical student mentees and distributed a dedicated questionnaire (pre- and post-mentorship) to compare mentees' self-reported cancer specialty knowledge and oncology career motivation after undertaking a 6-week mentorship. We also determined students' interest across specialties and subspecialties and measured mentor availability via percentage programme uptake. Statistical analysis included univariate inferential tests on SPSS software. Twentynine (23.4%) of 124 oncology specialists agreed to become mentors. The mentorship was completed by 30 students across three medical schools: 16 (53.3%) Barts, 10 (33.3%) Birmingham, and 4 (13.3%) King's; 11 (36.7%) mentored by medical oncologists, 10 (33.3%) by clinical/radiation oncologists, and 9 (30%) by surgical oncologists. The mentorship generated a statically significant increase in students' knowledge of the multidisciplinary team and all oncology-related specialties including academia/research but not interest towards a career in oncology. Undergraduate oncology mentoring is an effective educational, networking and motivational tool for medical students. Student societies are a valuable asset in cultivating medical student oncology interest by connecting students to faculty and increasing mentor accessibility. Further research should focus on developing an optimal mentorship structure and evaluating long-term outcomes of such educational initiatives.

The Rtr1p CTD phosphatase autoregulates its mRNA through a degradation pathway involving the REX exonucleases.

Rtr1p is a phosphatase that impacts gene expression by modulating the phosphorylation status of the C-terminal domain of the large subunit of RNA polymerase II. Here, we show that Rtr1p is a component of a novel mRNA degradation pathway that promotes its autoregulation through turnover of its own mRNA. We show that the 3'UTR of the RTR1 mRNA contains a cis element that destabilizes this mRNA. RTR1 mRNA turnover is achieved through binding of Rtr1p to the RTR1 mRNP in a manner that is dependent on this cis element. Genetic evidence shows that Rtr1p-mediated decay of the RTR1 mRNA involves the 5'-3' DExD/H-box RNA helicase Dhh1p and the 3'-5' exonucleases Rex2p and Rex3p. Rtr1p and Rex3p are found associated with Dhh1p, suggesting a model for recruiting the REX exonucleases to the RTR1 mRNA for degradation. Rtr1p-mediated decay potentially impacts additional transcripts, including the unspliced BMH2 pre-mRNA. We propose that Rtr1p may imprint its RNA targets cotranscriptionally and determine their downstream degradation mechanism by directing these transcripts to a novel turnover pathway that involves Rtr1p, Dhh1p, and the REX family of exonucleases.

TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis.

Upon activation, T cells undergo metabolic reprogramming to meet the bioenergetic demands of clonal expansion and effector function. Because dysregulated T cell cytokine production and metabolic phenotypes coexist in chronic inflammatory disease, including rheumatoid arthritis (RA), we investigated whether inflammatory cytokines released by differentiating T cells amplified their metabolic changes. We found that tumor necrosis factor-α (TNF-α) released by human naïve CD4+ T cells upon activation stimulated the expression of a metabolic transcriptome and increased glycolysis, amino acid uptake, mitochondrial oxidation of glutamine, and mitochondrial biogenesis. The effects of TNF-α were mediated by activation of Akt-mTOR signaling by the kinase ITK and did not require the NF-κB pathway. TNF-α stimulated the differentiation of naïve cells into proinflammatory T helper 1 (TH1) and TH17 cells, but not that of regulatory T cells. CD4+ T cells from patients with RA showed increased TNF-α production and consequent Akt phosphorylation upon activation. These cells also exhibited increased mitochondrial mass, particularly within proinflammatory T cell subsets implicated in disease. Together, these findings suggest that T cell-derived TNF-α drives their metabolic reprogramming by promoting signaling through ITK, Akt, and mTOR, which is dysregulated in autoinflammatory disease.

Retrospective analysis of SGLT2 inhibitors in heart failure with preserved ejection fraction.

AIMS: Heart failure (HF) is one of the leading causes of cardiovascular morbidity and mortality. HF with preserved ejection fraction (HFpEF), or diastolic failure, accounts for half of all HF cases and differs from HF with reduced ejection fraction (HFrEF). Patients with HFpEF are typically older, female, and commonly seen with chronic kidney disease (CKD), one of the leading independent risk factors for mortality in these patients. Unfortunately, drugs that had shown significant improvements in mortality in HFrEF have not shown similar benefits in HFpEF. Recently, sodium glucose transporter 2 inhibitors (SGLT2i) have been shown to reduce cardiovascular morbidity and mortality in HFrEF patients and slow down CKD progression. This study aimed to elucidate the impact of this drug class on mortality and risk of end stage renal disease in patients with HFpEF, which is currently unclear. METHODS AND RESULTS: We retrospectively analysed the Research Data Warehouse containing electronic health records from de-identified patients (n = 1 266 290) from the University of Mississippi Medical Center from 2013 to 2022. HFpEF patients had an average follow-up of 4 ± 2 years. Factors associated with increased all-cause mortality during HFpEF included age, male sex, and CKD. Interestingly, the only treatments associated with significant improvements in survival were angiotensin converting enzyme inhibitors/angiotensin receptor blockers and SGLT2i, regardless of CKD or diabetes status. Additionally, SGLT2i use was also associated with significant decrease in the risk of end stage renal disease. CONCLUSIONS: Our results support the use of SGLT2i in an HFpEF population with relatively high rates of hypertension, CKD, and black race and suggests that improvements in mortality may be through preserving kidney function.

Virtual Technology in Radiologic Technology Classrooms: Educational Effect of the COVID-19 Pandemic.

PURPOSE: To investigate the educational effect of the COVID-19 pandemic on virtual technology use in the radiologic technology classroom by comparing virtual technology use and perceived barriers for use from before the COVID-19 pandemic through the spring 2021 semester. METHODS: An explanatory mixed-method, cross-sectional survey design was used to evaluate radiologic technology educators' integration of virtual technology and continuance intention to use (CITU) virtual technology in the radiologic technology classroom. A pseudoqualitative component also was used to add meaning to the quantitative data. RESULTS: A total of 255 educators completed the survey. Educators with associate degrees scored significantly lower in CITU compared with participants with master's degrees (P = .04) and doctoral or professional degrees (P = .01). Virtual technology use significantly increased from before COVID-19 to spring 2021 (P < .001). Educators' perceptions of barriers to technology integration significantly decreased from before COVID-19 to spring 2021 (P < .001). In this report, radiologic technology educators indicated intentions for increased virtual technology use in the future compared with their use during the spring 2021 semester (P = .001). DISCUSSION: Virtual technology use was low before COVID-19, and although it increased during the spring 2021 semester, it remained relatively low. Future intentions for virtual technology use indicate an increase from spring 2021, suggesting a change in future delivery of radiologic science education. Instructors' levels of education had a significant effect on CITU scores. Cost and funding was consistently the highest reported barrier to virtual technology use, whereas student resistance to technology was consistently the lowest reported barrier. Narratives of participants' challenges, current and future use, and rewards related to virtual technology also added pseudoqualitative meaning to the quantitative findings. CONCLUSION: The educators in this study demonstrated low virtual technology use before the COVID-19 pandemic, increased virtual technology use because of the pandemic, and significantly positive CITU scores. Radiologic science educators' responses regarding their challenges, current and future use, and rewards might be helpful in facilitating more effective technology integration.

Effect of low-power laser irradiation on the shear bond strength and thermal changes across different zirconia thicknesses using different irradiation times.

PURPOSE: To investigate the effect of irradiation time and zirconia thickness using low power Er,Cr:YSGG laser irradiation (for debonding purposes) on the thermal changes and shear bond strength of resin-bonded 3% mol yttrium oxide stabilized tetragonal zirconia polycrystal (3Y-TZP) specimens. MATERIALS AND METHODS: 3Y-TZP slices of 0.5, 2, and 3 mm thick were used. The temperature during laser irradiation using single spot irradiation at different times (30, 60, 90, and 120 s) and line scanning irradiation from one spot tanother at three different distances (2-, 4-, and 6- mm) were recorded. Single spot and line scanning irradiation data were analyzed using three-way ANOVA (α: 0.05) and generalized linear mixed model, respectively. Non-irradiated (control) and irradiated resin-bonded 3Y-TZP specimens were shear tested, and the data were analyzed using two-way ANOVA (α: 0.05). RESULTS: Under single spot irradiation, the laser-induced temperature was higher through thin 3Y-TZP at any time compared to thick 3Y-TZP. For the line scanning method, short distances (2 and 4 mm) resulted in a significant increase in temperature in 0.5 mm thick specimens. Laser irradiation significantly decreased the shear bond strength of the 0.5 mm group compared to the non-irradiated group. After irradiation, the bond strength of the 2- and 3-mm thick 3Y-TZP was similar to the non-irradiated group. CONCLUSION: The temperature and bond strength of low-power laser irradiated 3Y-TZP specimens was affected by the specimen thickness but not by the irradiation time tested. Low-power laser irradiation is an effective debonding method for thin Y-TZP restorations.

Benefits of Mentoring in Oncology Education for Mentors and Mentees: Pre-Post Interventional Study of the British Oncology Network for Undergraduate Societies' National Oncology Mentorship Scheme.

BACKGROUND: Formal education of oncology is lacking in many undergraduate medical curricula. Mentoring schemes can expose participants to specific areas of medicine and may address the shortfalls in oncology education. Few mentoring schemes have been designed within the United Kingdom, especially within oncology. There is a need to understand reasons for mentor and mentee participation in such schemes and to identify ways to minimize barriers to engagement. OBJECTIVE: This study identifies motivations for participation in an oncology mentoring scheme and its benefits and limitations to both the mentee and the mentor. METHODS: The British Oncology Network for Undergraduate Societies launched a National Oncology Mentorship Scheme (NOMS) on September 1, 2021. Mentees (medical student or foundation doctor) were paired with mentors (specialty registrar or consultant), for 6 months of mentoring. In total, 86 mentors and 112 mentees were recruited to the scheme. The mentees and mentors were asked to meet at least 3 times during this period and suggestions were provided on the content of mentoring. Mentees and mentors were invited to complete a prescheme questionnaire, exploring motivations for involvement in the scheme, current experiences within oncology, and knowledge and interests in the field. At the end of the scheme, mentors and mentees were asked to complete a postscheme questionnaire exploring experiences and benefits or limitations of participation. Paired analysis was performed using the Wilcoxon signed-rank test. For free text data, content analysis was applied to summarize the main themes in the data. RESULTS: Of the 66 (59%) mentees who completed the prescheme questionnaire, 41 (62%) were clinical, 21 (32%) preclinical medical students, and the remainder were junior doctors. For mentees, networking was the primary reason for joining the scheme (n=25, 38%). Mentees ranked experience of oncology at medical school at 3 on 10 (IQR 2-5). In this, 46 (53%) mentors completed the prescheme questionnaire, 35 (76%) were registrar level, and the remainder were consultant level (n=11). The most common reason for mentor participation was to increase awareness and interest in the field (n=29, 63%). Of those who completed the prescheme questionnaire, 23 (35%) mentees and 25 (54%) mentors completed the postscheme questionnaire. Knowledge in all areas of oncology assessed significantly increased during the scheme (P<.001). Most mentees (n=21, 91%) and mentors (n=18, 72%) felt they had benefited from the scheme. Mentees cited gaining insights into oncology as most beneficial; and mentors, opportunities to develop professionally. Whilst mentees did not report any barriers to participating in the scheme, mentors stated lack of time as the greatest barrier to mentoring. CONCLUSIONS: British Oncology Network for Undergraduate Societies' NOMS is expanding and is beneficial for mentees through increasing knowledge, providing exposure, and career advice in oncology. Mentors benefit from improving their mentoring skills and personal satisfaction.

Geriatric Oncology as an Unmet Workforce Training Need in the United Kingdom-A Narrative Review by the British Oncology Network for Undergraduate Societies (BONUS) and the International Society of Geriatric Oncology (SIOG) UK Country Group.

Cancer is a disease associated with ageing. Managing cancer in older adults may prove challenging owing to pre-existing frailty, comorbidity, and wider holistic needs, as well as the unclear benefits and harms of standard treatment options. With the ongoing advances in oncology and the increasing complexity of treating older adults with cancer, the geriatric oncology field must be a priority for healthcare systems in education, research, and clinical practice. However, geriatric oncology is currently not formally taught in undergraduate education or postgraduate training programmes in the United Kingdom (UK). In this commentary, we outline the landscape of geriatric oncology undergraduate education and postgraduate training for UK doctors. We highlight current challenges and opportunities and provide practical recommendations for better preparing the medical workforce to meet the needs of the growing population of older adults with cancer. This includes key outcomes to be considered for inclusion within undergraduate and postgraduate curricula.

Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma.

T cells demonstrate impaired function in multiple myeloma (MM) but suppressive mechanisms in the bone marrow microenvironment remain poorly defined. We observe that bone marrow CD8+ T-cell function is decreased in MM compared with controls, and is also consistently lower within bone marrow samples than in matched peripheral blood samples. These changes are accompanied by decreased mitochondrial mass and markedly elevated long-chain fatty acid uptake. In vitro modeling confirmed that uptake of bone marrow lipids suppresses CD8+ T function, which is impaired in autologous bone marrow plasma but rescued by lipid removal. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8+ T cells in MM, and FATP1 blockade also rescued CD8+ T-cell function, thereby identifying this as a novel target to augment T-cell activity in MM. Finally, analysis of samples from cohorts of patients who had received treatment identified that CD8+ T-cell metabolic dysfunction resolves in patients with MM who are responsive to treatment but not in patients with relapsed MM, and is associated with substantial T-cell functional restoration.

Injuries of the Pectoralis Major: Diagnosis and Management.

Pectoralis major ruptures are uncommon injuries that have become more prevalent over the past 20 years due to increased participation in weight lifting. Patients often present with localized swelling and ecchymosis, muscular deformity, thinning of the anterior axillary fold, and weakness in adduction and internal rotation of the affected arm. History and physical is often augmented with radiology, magnetic resonance imaging of the chest being the gold standard. Nonoperative management is reserved for old patients with low functional demands. Operative intervention is the treatment of choice with improved functional outcomes, cosmesis, and patient satisfaction.

Identifying thresholds in air exposure, water temperature and fish size that determine reflex impairment in brook trout exposed to catch-and-release angling.

Understanding the factors that contribute to fish impairment and survival from angling events is essential to guide best angling practices for catch-and-release (C&R) recreational fisheries. Complex interactions often exist between angler behaviour, environmental conditions, and fish characteristics that ultimately determine biological outcomes for fish. Yet, few studies focus on identifying biologically relevant thresholds. We therefore examined the effects of water temperature, air exposure and fish size on reflex impairment and mortality in brook trout Salvelinus fontinalis exposed to experimental and simulated angling stressors (n = 337). Using conditional inference trees, we identified interactions among these factors as well as threshold values within them that determine brook trout reflex impairment as an indicator of whole animal stress. Specifically, longer air exposure times (>30 sec) and warmer temperatures (>19.5°C) had a synergistic effect leading to higher reflex impairment scores. Further, larger fish (>328 mm) were more sensitive to air exposure durations >10 sec. Of the reflex impairment measures, loss of equilibrium and time to regain equilibrium were strongly and moderately associated with brook trout mortality (18-24 h monitoring), although mortality rates were generally low (6%). These findings support previous research that has established strong links between these reflex impairment measures and fish health outcomes in other species. They also highlight the important interactions among air exposure duration, water temperature and fish size that determine impairment in brook trout, providing specific thresholds to guide best angling practices for C&R fisheries. This approach may be widely applicable to generate similar thresholds that can be encouraged by regulators and adopted by anglers for other common C&R fishes.

Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation.

Succinate dehydrogenase (SDH) loss-of-function mutations drive succinate accumulation in tumor microenvironments, for example in the neuroendocrine tumors pheochromocytoma (PC) and paraganglioma (PG). Control of innate immune cell activity by succinate is described, but effects on T cells have not been interrogated. Here we report that exposure of human CD4+ and CD8+ T cells to tumor-associated succinate concentrations suppresses degranulation and cytokine secretion, including of the key anti-tumor cytokine interferon-γ (IFN-γ). Mechanistically, this is associated with succinate uptake-partly via the monocarboxylate transporter 1 (MCT1)-inhibition of succinyl coenzyme A synthetase activity and impaired glucose flux through the tricarboxylic acid cycle. Consistently, pharmacological and genetic interventions restoring glucose oxidation rescue T cell function. Tumor RNA-sequencing data from patients with PC and PG reveal profound suppression of IFN-γ-induced genes in SDH-deficient tumors compared with those with other mutations, supporting a role for succinate in modulating the anti-tumor immune response in vivo.

Regression of Intraocular Rosai- Dorfman Disease Following Treatment with Photodynamic Therapy.

Rosai-Dorfman disease (RDD), a rare form of histiocytosis, has been reported to cause choroidal masses and subsequent serous retinal detachments. We present a case of RDD associated with a choroidal mass and retinal detachment that did not respond to corticosteroid treatment and regressed after treatment with photodynamic therapy (PDT). Following treatment, the patient had a successful anatomic and clinical outcome, with no recurrence of serous detachment and 20/25 visual acuity. This is the first report of choroidal RDD successfully treated with PDT. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:568-571.].

Loss of the nutrient sensor TAS1R3 leads to reduced bone resorption.

The taste receptor type 1 (TAS1R) family of heterotrimeric G protein-coupled receptors participates in monitoring energy and nutrient status. TAS1R member 3 (TAS1R3) is a bi-functional protein that recognizes amino acids such as L-glycine and L-glutamate or sweet molecules such as sucrose and fructose when dimerized with TAS1R member 1 (TAS1R1) or TAS1R member 2 (TAS1R2), respectively. It was recently reported that deletion of TAS1R3 expression in Tas1R3 mutant mice leads to increased cortical bone mass but the underlying cellular mechanism leading to this phenotype remains unclear. Here, we independently corroborate the increased thickness of cortical bone in femurs of 20-week-old male Tas1R3 mutant mice and confirm that Tas1R3 is expressed in the bone environment. Tas1R3 is expressed in undifferentiated bone marrow stromal cells (BMSCs) in vitro and its expression is maintained during BMP2-induced osteogenic differentiation. However, levels of the bone formation marker procollagen type I N-terminal propeptide (PINP) are unchanged in the serum of 20-week-old Tas1R3 mutant mice as compared to controls. In contrast, levels of the bone resorption marker collagen type I C-telopeptide are reduced greater than 60% in Tas1R3 mutant mice. Consistent with this, Tas1R3 and its putative signaling partner Tas1R2 are expressed in primary osteoclasts and their expression levels positively correlate with differentiation status. Collectively, these findings suggest that high bone mass in Tas1R3 mutant mice is due to uncoupled bone remodeling with reduced osteoclast function and provide rationale for future experiments examining the cell-type-dependent role for TAS1R family members in nutrient sensing in postnatal bone remodeling.

Understanding the individual to implement the ecosystem approach to fisheries management.

Ecosystem-based approaches to fisheries management (EAFMs) have emerged as requisite for sustainable use of fisheries resources. At the same time, however, there is a growing recognition of the degree of variation among individuals within a population, as well as the ecological consequences of this variation. Managing resources at an ecosystem level calls on practitioners to consider evolutionary processes, and ample evidence from the realm of fisheries science indicates that anthropogenic disturbance can drive changes in predominant character traits (e.g. size at maturity). Eco-evolutionary theory suggests that human-induced trait change and the modification of selective regimens might contribute to ecosystem dynamics at a similar magnitude to species extirpation, extinction and ecological dysfunction. Given the dynamic interaction between fisheries and target species via harvest and subsequent ecosystem consequences, we argue that individual diversity in genetic, physiological and behavioural traits are important considerations under EAFMs. Here, we examine the role of individual variation in a number of contexts relevant to fisheries management, including the potential ecological effects of rapid trait change. Using select examples, we highlight the extent of phenotypic diversity of individuals, as well as the ecological constraints on such diversity. We conclude that individual phenotypic diversity is a complex phenomenon that needs to be considered in EAFMs, with the ultimate realization that maintaining or increasing individual trait diversity may afford not only species, but also entire ecosystems, with enhanced resilience to environmental perturbations. Put simply, individuals are the foundation from which population- and ecosystem-level traits emerge and are therefore of central importance for the ecosystem-based approaches to fisheries management.