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Gamma delta (γδ) T cells reside within human tissues including tumors, but their function in mediating antitumor responses to immune checkpoint inhibition is unknown. Here we show that kidney cancers are infiltrated by Vδ2 − γδ T cells, with equivalent representation of Vδ1 + and Vδ1 − cells, that are distinct from γδ T cells found in normal human tissues. These tumor-resident Vδ2 − T cells can express the transcriptional program of exhausted αβ CD8 + T cells as well as canonical markers of terminal T-cell exhaustion including PD-1, TIGIT and TIM-3. Although Vδ2 − γδ T cells have reduced IL-2 production, they retain expression of cytolytic effector molecules and co-stimulatory receptors such as 4-1BB. Exhausted Vδ2 − γδ T cells are composed of three distinct populations that lack TCF7 , are clonally expanded and express cytotoxic molecules and multiple Vδ2 − T-cell receptors. Human tumor-derived Vδ2 − γδ T cells maintain cytotoxic function and pro-inflammatory cytokine secretion in vitro. The transcriptional program of Vδ2 − T cells in pretreatment tumor biopsies was used to predict subsequent clinical responses to PD-1 blockade in patients with cancer. Thus, Vδ2 − γδ T cells within the tumor microenvironment can contribute to antitumor efficacy. γδ T cells contribute to cancer immunity by killing tumor cells, but their function in the context of immune checkpoint inhibition is less clear. Here the authors show that a Vδ2 − subset of γδ T cells in human kidney tumors phenotypically resembles exhausted T cells yet retains this cytolytic function and can be used to predict response to immune checkpoint inhibition.

As climate change continues to threaten human and natural systems, the search for cost-effective and practical mitigation solutions is gaining momentum. Reforestation has recently been identified as a promising nature-based climate solution. Yet there are context-dependent biophysical, financial, land-use and operational constraints to reforestation that demand careful consideration. Here, we show that 121 million ha of presently degraded land in Southeast Asia, a region noted for its significant reforestation potential, are biophysically suitable for reforestation. Reforestation of this land would contribute 3.43 ± 1.29 PgCO2e yr−1 to climate mitigation through 2030. However, by taking a combination of on-the-ground financial, land use and operational constraints into account, we find that only a fraction of that mitigation potential may be achievable (0.3–18%). Such constraints are not insurmountable, but they show that careful planning and consideration are needed for effective landscape-scale reforestation.Reforestation has been recently identified as a promising climate mitigation option. In Southeast Asia, 120 million ha of land are biophysically suitable for reforestation. However, financial, land-use and operational factors constrain mitigation potential to a fraction of its total possible value.

Maternal depressive symptoms influence neurodevelopment in the offspring. Such effects may appear to be gender-dependent. The present study examined contributions of prenatal and postnatal maternal depressive symptoms to the volume and microstructure of the amygdala in 4.5-year-old boys and girls. Prenatal maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS) at 26 weeks of gestation. Postnatal maternal depression was assessed at 3 months using the EPDS and at 1, 2, 3 and 4.5 years using the Beck’s Depression Inventory-II. Structural magnetic resonance imaging and diffusion tensor imaging were performed with 4.5-year-old children to extract the volume and fractional anisotropy (FA) values of the amygdala. Our results showed that greater prenatal maternal depressive symptoms were associated with larger right amygdala volume in girls, but not in boys. Increased postnatal maternal depressive symptoms were associated with higher right amygdala FA in the overall sample and girls, but not in boys. These results support the role of variation in right amygdala structure in transmission of maternal depression to the offspring, particularly to girls. The differential effects of prenatal and postnatal maternal depressive symptoms on the volume and FA of the right amygdala suggest the importance of the timing of exposure to maternal depressive symptoms in brain development of girls. This further underscores the need for intervention targeting both prenatal and postnatal maternal depression to girls in preventing adverse child outcomes.

Mechanisms underlying the profound parental effects on cognitive, emotional and social development in humans remain poorly understood. Studies with nonhuman models suggest variations in parental care affect the limbic system, influential to learning, autobiography and emotional regulation. In some research, nonoptimal care relates to decreases in neurogenesis, although other work suggests early-postnatal social adversity accelerates the maturation of limbic structures associated with emotional learning. We explored whether maternal sensitivity predicts human limbic system development and functional connectivity patterns in a small sample of human infants. When infants were 6 months of age, 20 mother–infant dyads attended a laboratory-based observational session and the infants underwent neuroimaging at the same age. After considering age at imaging, household income and postnatal maternal anxiety, regression analyses demonstrated significant indirect associations between maternal sensitivity and bilateral hippocampal volume at six months, with the majority of associations between sensitivity and the amygdala demonstrating similar indirect, but not significant results. Moreover, functional analyses revealed direct associations between maternal sensitivity and connectivity between the hippocampus and areas important for emotional regulation and socio-emotional functioning. Sensitivity additionally predicted indirect associations between limbic structures and regions related to autobiographical memory. Our volumetric results are consistent with research indicating accelerated limbic development in response to early social adversity, and in combination with our functional results, if replicated in a larger sample, may suggest that subtle, but important, variations in maternal care influence neuroanatomical trajectories important to future cognitive and emotional functioning.

BackgroundSoft-tissue sarcomas (STS) are a rare group of mesenchymal malignancies that account for approximately 1% of adult human cancer. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common subtypes of adult STS. Clinical stratification of UPS patients has not evolved for decades and continues to rely on tumor-centric metrics including tumor size and depth. Our understanding of how the tumor microenvironment correlates to these clinicopathologic parameters remains limited.MethodsHere, we performed single-cell flow cytometric immune-based profiling of 15 freshly resected UPS tumors and integrated this analysis with clinical, histopathologic, and outcomes data using both a prospective and retrospective cohort of UPS patients.ResultsWe uncovered a correlation between physiologic and anatomic properties of UPS tumors and the composition of immune cells in the tumor microenvironment. Specifically, we identified an inverse correlation between tumor-infiltrating CD8 + T cells and UPS tumor size; and a positive correlation between tumor-infiltrating CD8 + T cells and overall survival. Moreover, we demonstrate an association between anatomical location (deep or superficial) and frequency of CD4 + PD1hi infiltrating T cells in UPS tumors.ConclusionsOur study provides an immune-based analysis of the tumor microenvironment in UPS patients and describes the different composition of tumor infiltrating lymphocytes based on size and tumor depth.

p53 tumor suppressor is a subject of several post-translational modifications, including phosphorylation, ubiquitination and acetylation, which regulate p53 function. A new covalent modification of p53 at lysine 386 by SUMO-1 was recently identified. To elucidate the function of sumoylated p53, we compared the properties of wild type p53 and sumoylation-deficient p53 mutant, K386R. No differences were found between wild type p53 and K386R mutant of p53 in transactivation or growth suppression assays. Moreover, overexpression of SUMO-1 has no effect on p53-regulated transcription. Biochemical fractionation showed that sumoylated p53 is localized in the nucleus and is tightly bound to chromatin structures. p53 and SUMO-1 co-localized in PML nuclear bodies in 293 cells and the nucleoli in MCF7 and HT1080 cells. However, sumoylation-deficient p53 mutant showed a similar pattern of intranuclear localization, suggesting that SUMO-1 does not target p53 to subnuclear structures. These data indicate that SUMO-1 modification of p53 at lysine 386 may not be essential for p53's cellular localization, transcriptional activation, or growth regulation.

BackgroundThere is no clear consensus on when patients with surgically treated right ankle fractures can return to car driving, or how best to assess their fitness to drive. Through a rigorous driving assessment program consisting of both off-road and on-road tests, we aim to determine if these patients are able to pass a standard driving test, even before weight bearing has been initiated.MethodsA prospective grant-funded (Supported by AOTrauma Asia Pacific Ref: AOTAP12-17) clinical study was conducted. Patients aged 25–65 years who underwent surgery for right ankle fractures and held a valid motorcar driving license were recruited in a single institution from 2013 to 2015. The surgeon and a specialist occupational therapist assessed the patients at 2, 6 and 12 weeks post-surgery. A Short Musculoskeletal Functional Assessment (SMFA) Questionnaire was administered and the brake reaction time was measured using a driving simulator. Patients who met the minimal criteria were then subjected to a full on-road driving test in a real-world environment with a driving instructor. A follow-up telephone questionnaire was administered at least 6 months after return to driving to determine if patients had returned to driving safely.ResultsA total of 23 patients (8 females, 15 males) were recruited. The mean age was 42.8 (± 12.9) years. There was a significant improvement in the SMFA (p < 0.05) and braking time (p < 0.05) at 6 and 12 weeks post-surgery. Nearly all (91%) patients passed the on-road driving test at 6 weeks, before their fractures had healed or weight bearing was initiated. The questionnaire administered at least 6 months after return to driving revealed that all patients had returned to regular driving safely.ConclusionWe conclude that patients with isolated, surgically treated right ankle fractures can successfully pass a standard driving test at 6 weeks post-surgery, even before weight bearing has been initiated. We also showed that the ability to drive correlates with improvements in the SMFA scores and braking times.Level of evidenceII.

Health literacy encompasses the social and cognitive skills required to access, comprehend, and use health information to maintain or improve health. This is the first study to assess the health literacy levels of health science students and adult residents in Singapore using the health literacy questionnaire (HLQ) and compare their levels. A cross-sectional survey was conducted in Singapore from December 2019 to January 2023. The 44-item HLQ was administered to (1) entry-level health science students in a local university and (2) adult residents aged 18 and 80 who could understand and respond in English, Mandarin, or Malay. Variables such as demographic data, gender, age, language(s) spoken, education levels, and employment status were collected. HLQ scores were analysed using descriptive statistics, Mann-Whitney U-test, and rank-biserial coefficient. Two hundred and eighty-two surveys were returned (students,  = 112; residents,  = 170). Overall, the health science students, particularly the female subgroup, obtained higher mean HLQ scores than the residents. Conversely, male residents scored better in 5 of the 9 subscales. Most comparisons lack statistical significance despite the noticeable effect sizes. Health science students have better health literacy when navigating health information. However, the lack of significant difference between groups for most HLQ scales, especially when comparing within age groups, indicated that the health science students needed to be more confident in their health literacy skills.

This is a study on the demographics and clinical outcomes including the response to therapy of patients with focal segmental glomerulosclerosis (FSGS) over the past decade. All histologically proven FSGS cases diagnosed between 2008 and 2018 were analyzed for their clinical, laboratory, and histological characteristics including treatment that could influence the disease progression and renal outcome of these patients. We used the Columbia Classification for FSGS for the renal biopsy. There were two subgroups of FSGS patients; those with nephrotic syndrome and those without nephrotic syndrome. Patients with FSGS with non-nephrotic syndrome had poorer survival rates compared to the nephrotic group. For those without nephrotic syndrome, the indices responsible for progression involved more tubular and blood vessel lesions in addition to glomerular pathology compared to those with nephrotic syndrome. Patients with FSGS with nephrotic syndrome responded to immunosuppressants more favorably compared to the non-nephrotic group, though both groups responded with decreasing proteinuria. The nephrotic group had a better 10-year long-term survival rate of 92 vs. 72% for the non-nephrotic group (log-rank 0.002). The 10-year survival for the whole group of FSGS patients was 64%. Our data suggest that in FSGS, one of the significant components of the disease is the vascular and tubular damage, apart from the underlying glomerular pathology, resulting in varying responses to therapy, and the difference is reflected in inherently poorer response to immunosuppressant therapy in those without nephrotic syndrome as opposed to those with nephrotic syndrome, who responded to immunosuppressant therapy (IST) with stabilization of renal function and had less blood vessel and tubular lesions.

Singapore's large aging population poses significant challenges for the health care system in managing cognitive decline, underscoring the importance of identifying and implementing effective interventions. Cognitive training delivered remotely as a digital therapeutic (DTx) may serve as a scalable and accessible approach to overcoming these challenges. While previous studies indicate the potential of cognitive training as a promising solution for managing cognitive decline, understanding the attitudes and experiences of older adults toward using such DTx platforms remains relatively unexplored. This study aimed to characterize the general acceptability and user experience of CURATE.DTx, a multitasking-based DTx platform that challenges the cognitive domains of attention, problem-solving, and executive function in the Singaporean older adult population. A total of 15 older adult participants (mean age 66.1, SD 3.5 years) were recruited for a 90-minute in-person session. This session included a 30-minute playtest of CURATE.DTx, followed by a 60-minute semistructured interview to understand their overall attitudes, experience, motivation, and views of the intervention. Interviews were audio-recorded and transcribed verbatim, then analyzed using an inductive approach. Thematic analysis was used to identify emerging patterns and insights. A total of 3 main themes, and their respective subthemes, emerged from the interviews: comprehension, with subthemes of instruction and task comprehension; acceptability, with subthemes of tablet usability, engagement and enjoyment, and attitude and perceived benefits; and facilitators to adoption, with subthemes of framing and aesthetics, motivation recommendations and the role of medical professionals. Our findings revealed that participants encountered some challenges with understanding certain elements of CURATE.DTx. Nevertheless, they were still highly engaged with it, finding the challenge to be enjoyable. Participants also showed a strong awareness of the importance of cognitive training and expressed a keen interest in using CURATE.DTx for this purpose, especially if recommended by medical professionals. Given the positive engagement and feedback obtained from Singaporean older adults on CURATE.DTx, this study can serve as a basis for future platform iterations and strategies that should be considered during implementation. Future studies should continue implementing an iterative codesign approach to ensure the broader applicability and effectiveness of interventions tailored to this demographic.