Female Donors Research Articles

Afterload mismatch is associated with gender mismatch and negatively affect long-term outcome after heart transplant

Abstract Background Cardiac physiology changes after heart transplant (HT), resulting in a restrictive physiology with an increase in both arterial elastance (Ea) and ventricular elastance (Ees). This leads to a higher susceptibility to develop afterload mismatch, although the early identification of this phenomenon has not yet been explored. The aim of this study is to identify the presence of afterload mismatch after HT, its determinants, and its impact on cardiac mortality. Methods We conducted an observational, single-centre study based on the historical cohort of patients who underwent HT from 1985 to 2015 at our institution. We included patients who had survived the first year after HT with left ventricular ejection fraction (LVEF) ≥ 50%, International Society of Heart and Lung Transplantation (ISHLT) cardiac allograft vasculopathy of grade 0-1, and ISHLT acute cellular rejection of grade 0-1R at 1 year after HT. Ea and Ees were calculated using a non-invasive method based on blood pressure and end-systolic volume and end-diastolic volume measured at transthoracic echocardiography. Patients were grouped in 3 categories according to the presence of increased afterload and afterload mismatch as follows: low afterload (LA - Ea lower the median), matched high afterload (MHA - Ea higher of equal than the median, Ees higher or equal than the median), afterload mismatch (AM - Ea higher or equal than the median, Ees lower than the median). The impact of AM on long-term outcome, defined as cardiac mortality, was investigated, as well as predictors of AM. Results The study cohort consisted of 345 HT patients. The median of Ea and Ees were 4.0mmHg/mL and 6.75mmHg/mL, respectively. 49 patients (13%) developed AM, while LA and MHA groups accounted for 49% and 36% of the cohort, respectively. Patients with AM were mostly male (91%), with ischemic heart disease (45%) and a higher percentage of left ventricular assisted device prior to HT (8%). LVEF was lower in AM (57% vs 63% and 64% for LA and MHA respectively, p < 0.0001), while stroke volume was lower than LA and similar to MHA (27ml vs 35mL and 26mL for LA and MHA respectively, p = 0.0001). Predictors of AM were male recipient from male donor (Mr/Md) (β 015, p = 0.0067) and Mr from female donor (Mr/Fd) (β 0.6, p = 0.0078). After a median of 11.3-year follow-up, 59 (17%) HT recipients died. Cardiac mortality was higher in AM than in the other groups (AM median survival 17.2y vs 27.8y and 24.1y for LA and MHA respectively, log-rank p = 0.005). After adjusting for confounding variables, AM was a predictor of cardiac mortality (HR: 2.26; 95%CI 1.18 – 4.35), such as Mr/Fd (HR 2.94; 95%CI 1.18 – 4.35, p = 0.0358). Conclusion AM, in the context of a normal LVEF, is associated with male donor and sex mismatch, and negatively affects long-term outcome after HT.KM curvesCox proportional hazard model

Long-term outcomes of heart re-transplantation from HCV-viremic donors based on UNOS registry

Abstract Background The use of hepatitis C virus (HCV) viremic donors increased the heart donor pool, and reduced waitlist time and mortality among first-time single-organ heart transplant (HT) candidates without compromising their post-transplant survival. The outcomes of heart re-transplantation (re-HT) with the use of HCV-viremic donor grafts have not been investigated. Methods Using the United Network of Organ Sharing (UNOS) Registry we analyzed all adult patients who underwent single-organ heart re-HT in the United States between January 1, 2016, and December 31, 2022. HCV-viremic donors were defined by a positive nucleic acid amplification test (NAT+). Graft survival rates between HCV-viremic and HCV-non-viremic donor graft recipients were compared using a log rank test. Results During the study period, of 18,259 HTs performed, 427 (2.3%) constituted single-organ heart re-transplantations. Recipients of NAT+ grafts (n=19) compared to NAT- grafts (n=408) were more often male (84.2% vs 61.3%, p=0.04). Otherwise, there were no significant differences between the two groups in age, ethnicity, BMI, blood type, history of diabetes rates or stroke, creatinine or bilirubin levels, reason for re-HT, hemodynamics, use of mechanical circulatory support, and waitlist time. Ischemic time, frequency of female donors, HLA, ABO, CMV mismatch rates, and calculated panel reactive antibodies levels were comparable across the two groups. There were no significant differences in demographics or comorbidities rates between HCV-viremic and HCV-non-viremic donors apart from the cause of death. Among the donors of HCV-viremic grafts brain anoxia was reported more often (89.5%) than among HCV-non-viremic donors (40%), p <0.01. Rates of acute rejection treated in the first year after re-HT were comparable across the two groups. Over a mean follow-up of 3.0±2.1 and 3.3±1.8 years after re-HT from NAT- and NAT+ organ donors, respectively, graft survival rate at 1 year was 82% vs. 95% (p=0.3) and at 3 years 79% vs. 89%, respectively (p=0.6) (Figure). Conclusion Graft survival rates at 1 and 3 years post-heart re-HT in adult recipients of HCV-viremic donor grafts were comparable to those of recipients of HCV-non-viremic donor grafts. The current study provides compelling preliminary evidence that HCV-viremic donors constitute a viable donor pool for patients in need of heart re-transplantation.

Maternal dysbiosis produces long-lasting behavioral changes in offspring.

Advanced maternal age (AMA) is defined as a pregnancy in a woman older than 35 years of age. AMA increases the risk for both maternal and neonatal complications, including miscarriage and stillbirth. AMA has also been linked to neurodevelopmental and neuropsychiatric disorders in the offspring. Recent studies have found that age-associated compositional shifts in the gut microbiota contribute to altered microbial metabolism and enhanced inflammation in the host. We investigated the specific contribution of the maternal microbiome on pregnancy outcomes and offspring behavior by recolonizing young female mice with aged female microbiome prior to pregnancy. We discovered that pre-pregnancy colonization of young dams with microbiome from aged female donors significantly increased fetal loss. There were significant differences in the composition of the gut microbiome in pups born from dams recolonized with aged female biome that persisted through middle age. Offspring born from dams colonized with aged microbiome also had significant changes in levels of neurotransmitters and metabolites in the blood and the brain. Adult offspring from dams colonized with an aged microbiome displayed persistent depressive- and anxiety-like phenotypes. Collectively, these results demonstrate that age-related changes in the composition of the maternal gut microbiome contribute to chronic alterations in the behavior and physiology of offspring. This work highlights the potential of microbiome-targeted approaches, even prior to birth, may reduce the risk of neuropsychiatric disorders.

In vitro growth of secondary follicles from cryopreserved-thawed ovarian cortex.

Can secondary follicles be obtained from cultured cryopreserved-thawed human ovarian cortical tissue? We obtained high-quality secondary follicles from cultured cryopreserved-thawed human ovarian cortical tissue from cis female donors (cOVA), but not from trans masculine donors (tOVA) in the same culture conditions. The in vitro growth of oocytes present in unilaminar follicles into metaphase II stage (MII) oocytes has been previously achieved starting from freshly obtained ovarian cortical tissue from adult cis female donors. This involved a multi-step culture protocol and the first step included the transition from unilaminar follicles to multilayered secondary follicles. Given that the ovarian cortex (from both cis female and trans masculine donors) used for fertility preservation is cryopreserved, it is crucial to investigate the potential of unilaminar follicles from cryopreserved-thawed ovarian cortex to grow in culture. Cryopreserved-thawed ovarian cortical tissue from adult trans masculine donors (n = 3) and adult cis female donors (n = 3) was used for in vitro culture following the first culture step described in two published culture protocols (7-8 days and 21 days) and compared to freshly isolated ovarian cortex from trans masculine donors (n = 3) and to ovarian cortex prior to culture. Ovarian cortical tissue was obtained from adult trans masculine donors undergoing gender-affirming surgery while using testosterone, and from adult cis female donors undergoing oophorectomy for fertility preservation purposes before chemotherapy. The ovarian cortex was fixed either prior (day 0) or after the culture period. Follicular survival, growth, and morphology were assessed through histology and immunofluorescence. We quantified the different stages of follicular development (primordial, primary, secondary, and atretic) after culture and observed an increase in the percentage of secondary follicles as well as an increase in COLIV deposition in the stromal compartment regardless of the culture media used. The quality of the secondary follicles obtained from cOVA was comparable to those prior to culture. However, in the same culture conditions, the secondary follicles from tOVA (fresh and cryo) showed low-quality secondary follicles, containing oocytes with small diameter, granulosa cells that expressed abnormal levels of KRT19 and steroidogenic-marker STAR and lacked ACTA2+ theca cells, when compared to tOVA secondary follicles prior to culture. The number of different donors used was limited. Our study revealed that cryopreserved-thawed cOVA can be used to generate high-quality secondary follicles after culture and those can now be further tested to evaluate their potential to generate functional MII oocytes that could be used in the clinic. However, using the same culture protocol on tOVA (fresh and cryo) did not yield high-quality secondary follicles, suggesting that either the testosterone treatment affects follicular quality or adapted culture protocols are necessary to obtain high-quality secondary follicles from tOVA. Importantly, caution must be taken when using tOVA to optimize folliculogenesis in vitro. This research was funded by the European Research Council Consolidator Grant OVOGROWTH (ERC-CoG-2016-725722 to J.S.D.V. and S.M.C.D.S.L.), the Novo Nordisk Foundation (reNEW NNF21CC0073729 to H.C., F.W., J.S.D.V., S.M.C.D.S.L.), and China Scholarship Council (CSC 202008320362 and CSC 202008450034 to H.C. and F.W.), respectively. The authors have no conflicts of interest to declare. N/A.

Establishing an induced pluripotent stem cell line (SDPHi006-A) from a healthy Chinese female donor represents an accomplishment

We isolated peripheral blood mononuclear cells (PBMCs) from a healthy female donor, and successfully converted into induced pluripotent stem cells (iPSCs) by using non-integrating episomal vectors. These iPSCs displayed a normal karyotype, expressed markers of pluripotency, and showed the capacity to differentiate into three germ layers in vitro, which could be utilized for future research endeavors.

Establishment of an induced pluripotent stem cell line (SDCHi011-A) from a healthy Chinese female donor

We generated an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells (PBMCs) of a healthy 40-year-old Chinese Han female, using non-integrated reprogramming technology. The established iPSC line, SDCHi011-A, expressed pluripotency marker and could differentiate into cells of three germ layers in vitro with normal karyotype. This cell line is a valuable resource as a control line for stem cell research of disease models and molecular pathogenesis.

Association of regular plasmapheresis donation with serum protein and electrolyte levels: a multicentre cross-sectional study in China

BackgroundChina’s plasmapheresis donation policy differs from that of Western countries. The association between regular plasmapheresis donation and donor health in China is still unknown.ObjectivesTo investigate the association of regular plasmapheresis...

NMR Insights into Lipoprotein Particles: analyzing correlations with traditional lipid measurements

Abstract Introduction Lipid metabolism plays a crucial role in various physiological processes. Lipid molecules are transported by lipoproteins, and the intricate involvement of lipoproteins in cardiovascular disease (CVD) is well-established, given their diverse size, density, and lipid composition. The emergence of Nuclear Magnetic Resonance (NMR) spectroscopy, a high-resolution analytical technique, promotes the assessment of lipoprotein particle numbers and sizes. Studies suggest that the measurement of total low-density lipoprotein particle numbers (LDL-P), small LDL-P (SLDL-P), and total high-density lipoprotein particle numbers (HDL-P) provides better evaluation of risk of CVD than enzymatic-based measurements of LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C). Our study examined the correlation between NMR-derived lipoprotein profiles and traditional cholesterol measurements in control and patient populations. Methods Fasting serum samples were collected from healthy male and female donors (n=148), ages 21-64 years. The analysis also included the results from >20,000 patients’ samples submitted to our laboratory for NMR lipid testing. We assessed LDL-P, SLDL-P, HDL-P, large HDL (LHDL-P), and HDL size (HDL-S) by NMR. In addition, total cholesterol (TC) and HDL-C were measured using traditional automated enzymatic assays (Roche Diagnostics); LDL-C was calculated. Statistical analyses, including Spearman correlation, were performed using GraphPad Prism software. Spearman coefficient (r) ≥0.75 indicated a strong correlation, r <0.5 indicated a weak correlation. Results HDL-C only moderately correlated with total HDL-P in samples collected from controls (rcontrols=0.52) and patients (rpatients=0.68), while showing better correlation with LHDL-P (rcontrols=0.90, rpatients=0.89). Traditional LDL-C strongly correlated with total LDL-P (rcontrols=0.76, rpatients=0.81), but showed only weak correlation with SLDL-P (rcontrols=0.42, rpatients=0.28), which is considered more atherogenic and predictive of CVD risk than LDL-C or total LDL-P. Interestingly, among various lipoprotein parameters, SLDL-P correlated the strongest with HDL-S in both study populations (rcontrols=-0.87, rpatients=-0.84). Samples with higher number of SLDL-P also had smaller size of HDL-P, although the number of total HDL-P did not differ between high vs low SLDL-P samples. In contrast, only moderate negative correlation was observed between SLDL-P and traditional HDL-C (rcontrols=-0.74, rpatients=-0.68), suggesting that the size of HDL particles might add value in evaluating CVD risk. Conclusion The NMR technology has advantage over traditional measurements in stratifying an individual’s lipoprotein milieu. It provides insights into the number of small LDL particles and size of HDL particles, which are not included in standard lipid testing and may allow for more individualized patient care. Incorporation of lipoprotein size and particle number in clinical guidelines may help physicians with assessment CVD risk and treatment monitoring.

Integrated multimodal cell atlas of Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia in older adults. Although AD progression is characterized by stereotyped accumulation of proteinopathies, the affected cellular populations remain understudied. Here we use multiomics, spatial genomics and reference atlases from the BRAIN Initiative to study middle temporal gyrus cell types in 84 donors with varying AD pathologies. This cohort includes 33 male donors and 51 female donors, with an average age at time of death of 88 years. We used quantitative neuropathology to place donors along a disease pseudoprogression score. Pseudoprogression analysis revealed two disease phases: an early phase with a slow increase in pathology, presence of inflammatory microglia, reactive astrocytes, loss of somatostatin+ inhibitory neurons, and a remyelination response by oligodendrocyte precursor cells; and a later phase with exponential increase in pathology, loss of excitatory neurons and Pvalb+ and Vip+ inhibitory neuron subtypes. These findings were replicated in other major AD studies.

Prevalence, incidence, and residual risk for human immunodeficiency virus among blood donors from 2003 to 2022 in Guangzhou, China.

China's significant population affected by HIV poses a substantial threat to blood transfusion safety. Despite advancements in blood testing techniques, a residual risk of HIV transmission persists. Accurately assessing HIV epidemic and the residual risk is vital for monitoring blood supply safety and evaluating the effectiveness of new screening tests. We conducted a retrospective analysis of HIV detection results among voluntary blood donors from 2003 to 2022. The study included data on HIV-confirmed positive donors, HIV prevalence, infection risk factors, and an incidence-window period mathematical model to estimate the residual risk of HIV. Between 2003 and 2022, HIV prevalence among blood donors in Guangzhou showed a peak-shaped trend, initially increasing before declining. The overall HIV prevalence was 18.9 infections per 100,000 donations. Male donors had a significantly higher prevalence compared with female donors. Donors aged 26-35 years had the highest prevalence. Ethnic minority donors had a higher prevalence compared with Han donors. Repeat donors had a lower prevalence compared with first-time donors. Donors from other provinces had a higher prevalence compared with local donors. During the period of 2003 to 2022, the residual risk of HIV in Guangzhou steadily decreased, reaching a notable 1 in 526,316 donations in the past two years. The HIV epidemic among blood donors in Guangzhou remains severe, but the residual risk of HIV is decreasing. Novel detection methods have proven advantageous in reducing this residual risk. Implementing additional effective measures is imperative to ensure blood safety and curb the spread of HIV.

Evaluation of Female Recipient Infertility and Donor Spermatogonial Purification for Germ Cell Transplantation in Paralichthys olivaceus.

Since the advent of germ cell transplantation (GCT), it has been widely used in shortening the fish breeding cycle, sex-controlled breeding and the protection of rare and endangered fish. In this study, the effectiveness of female sterile recipient preparation and donor stem cell isolation and purification were comprehensively evaluated for spermatogonial stem cell transplantation (SSCT) in Paralichthys olivaceus. The best way to prepare sterile recipients was found to be giving three-year-old fish four intraovarian injections of busulfan (20 mg/kg body weight) combined with exposure to a high temperature (28 °C) after the spawning season compared with the two other ways, which induced apoptosis of most of the endogenous germ cells, resulting in shrinkage of the spawning plate and enlargement of the ovarian lumen. Further analysis showed that both the gonadosomatic index and germ-cell-specific vasa expression were significantly lower than those of the natural-temperature group before treatment (p < 0.05). A high percentage (>60.00%) of spermatogonial stem cells (SSCs) were obtained after isolation and purification and were transplanted into the prepared recipients. After three weeks of SSCT, the numbers of PKH26-labeled SSCs were increased in the ovaries of the recipients. These findings provide a basis for the establishment of an ideal SSCT technique using P. olivaceus females as the recipients, ultimately contributing to the efficient conservation of male germplasm resources and effective breeding.

7881 Using Selective Estrogen Receptor Modulators to Reveal Therapeutic Vulnerabilities in ESR1 Mutant Breast Cancer

Abstract Disclosure: S.W. Fanning: Grant Recipient; Self; Olema Oncology. Hotspot activating somatic mutations to ESR1, the gene for estrogen receptor alpha (ER), enable hormone therapy resistance and drive breast cancer metastasis. The Y537S missense mutation within the ER ligand binding domain is the most activating, therapy resistant, and increases metastatic potential. Next generation antiestrogens including lasofoxifene (laso) and elacestrant (RAD1901) show improved progression-free survival over fulvestrant (fulv), but further progress is needed to achieve durable response. To fully address Y537S ESR1, it is critically important to understand how the mutation boosts metastasis. We have developed a small molecule antiestrogen, T6I-29, that uniquely impacts transcriptional pathways related to cell-cell adhesions and morphology. Two allele-specific phenotypes identified by the Oesterreich Laboratory enhance the metastasis of Y537S ESR1 breast cancer cells. T6I-29-specific pathway effects were driven by a significant downregulation of dickkopf-1 (DKK1), which was also observed but to a lesser extent with fulv, laso, and RAD1901. DKK1 is an immunosuppressive, tumor-secreted glycoprotein and its overexpression correlates with poor outcomes in multiple cancers. However, DKK1 acts as a tumor-suppressor in colorectal cancer, which does not rely on ER. Our preliminary studies suggest that DKK1 plays a role in ER+ breast cancer progression. We measured significantly elevated DKK1 protein levels in the blood plasma of 108 diverse ER+ breast cancer patients compared to 100 matched healthy female donors and levels increase coincident with tumor stage. Unfortunately, we lack ESR1 mutation status and other critical details to make further insights on these patients. DKK1 gene expression and protein secretion is stimulated in WT cells by the pathogenic hormone 17β-estradiol (E2), while it is constitutively expressed in Y537S ESR1 cells. DKK1 is characterized as a WNT antagonist but can also induce PI3K/Akt signaling. Interestingly, DKK1 is elevated and ERα responsive in WT not mutant PI3KCA cell lines. DKK1 knockdown also reduced proliferation of Y537S ESR1 breast cancer cells where elevated DKK1 was observed. Presentation: 6/3/2024

Related Factors of Syphilis Positive Rate in Blood Donors During the COVID-19 Epidemic.

In Shenzhen of China, the continuous increase of syphilis infections threatens the safety of blood transfusion. In 2020, COVID-19 was discovered and spread rapidly around the world, and affected the prevalence of syphilis among blood donors. From 2013 to 2020, there were 839,161 blood samples collected in the Shenzhen Blood Center. Blood samples were screened by ELISA tests and confirmed by the TPPA (Treponema pallidum particle agglutination) tests and the TRUST (toluidine red unheated serum tests). All data was analyzed by the chi-square test. From 2013 to 2020, the positive rate of syphilis among blood donors varied significantly among individuals in different ages, educational backgrounds, regions, and blood donation histories (P<0.001). In 2020, It was the first time that there were more repeat blood donors than first-time blood donors and more blood donors with a higher education level than those with a lower education level, and the lowest reactive and positive rate of syphilis among blood donors was observed. Compared to 2019, the prevalence of syphilis among female and repeat blood donors decreased significantly in 2020 (P<0.01). The prevalence of syphilis in blood donors is related to the characteristics of blood donors (in addition to gender) and the COVID-19 epidemic. COVID-19 can affect the prevalence of syphilis among blood donors by influencing the composition of blood donors and the number of syphile-positive donors in certain blood donors, including female and repeat blood donors.

Sex-biased human thymic architecture guides Tcell development through spatially defined niches.

Within the thymus, regulation of the cellular crosstalk directing Tcell development depends on spatial interactions within specialized niches. To create a spatially defined map of tissue niches guiding humanpostnatal Tcell development, we employed the multidimensional imaging platform co-detection by indexing (CODEX) as well as cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) and assay for transposase accessible chromatin sequencing (ATAC-seq). We generated age-matched 4- to 5-month-old human postnatal thymus datasets for male and female donors, identifying significant sex differences in both Tcell and thymus biology. We demonstrate a possible role for JAG ligands in directing thymic-like dendritic cell development, identify important functions of a population ofextracellular matrix (ECM)- fibroblasts, and characterize the medullary niches surrounding Hassall's corpuscles. Together, these data represent an age-matched spatial multiomic resource to investigate how sex-based differences in thymus regulation and Tcell development arise, providing an essential resource to understand the mechanisms underlying immune function and dysfunction in males and females.

H-Loop Knotless Double-Row Repair Versus Krackow Repair for Achilles Tendon Rupture: A Biomechanical Study in a Cadaveric Model.

Surgery is widely recognized as an effective treatment for Achilles tendon rupture; however, there remains debate regarding the optimal surgical approach. To compare the biomechanical properties of 2 techniques, the H-loop knotless double-row (HLDR) suture repair and the Krackow suture repair, for Achilles tendon rupture in a cadaveric model. Controlled laboratory study. Ten matched Achilles tendon specimens from 5 male and 5 female donors were obtained. Each specimen from a matched pair was randomly distributed to 1 of 2 repair groups, the HLDR group or the Krackow group. Tendon elongation was recorded after exposure to 10, 100, 200, 400, 600, 800, and 1000 load cycles. The gap distance after application of a 100-N force, the force needed to produce a 2-mm gap, and the load to failure were measured. All biomechanical properties were compared between the HLDR and Krackow groups using the paired t test. The HLDR group consistently exhibited significantly less elongation than the Krackow group after exposure to the 7 load cycles (P < .01 for all). In addition, the HLDR group exhibited a significantly smaller gap distance after applying a 100-N force (0.30 ± 0.02 vs 8.10 ± 0.46 mm for Krackow group), required significantly more force to generate a 2-mm gap (419.68 ± 39.48 vs 22.29 ± 3.40 N for the Krackow group), and had a significantly higher ultimate failure load (519.91 ± 57.29 vs 220.30 ± 19.27 N for the Krackow group) (P < .01 for all). The study findings demonstrated that the HLDR technique had more advantages compared with the Krackow technique with regard to elongation after different cyclic loadings, gap distance after a 100-N load, force needed to produce a 2-mm gap, and load to failure in a cadaveric model. The HLDR technique could be a viable option for Achilles tendon rupture repair.

Deep learning assessment of senescence-associated nuclear morphologies in mammary tissue from healthy female donors to predict future risk of breast cancer: a retrospective cohort study

Cellular senescence has been associated with cancer as either a barrier mechanism restricting autonomous cell proliferation or a tumour-promoting microenvironmental mechanism that secretes proinflammatory paracrine factors. With most work done in non-human models and the heterogeneous nature of senescence, the precise role of senescent cells in the development of cancer in humans is not well understood. Furthermore, more than 1 million non-malignant breast biopsies are taken every year that could be a major resource for risk stratification. We aimed to explore the clinical relevance for breast cancer development of markers of senescence in mammary tissue from healthy female donors. In this retrospective cohort study, we applied single-cell deep learning senescence predictors, based on nuclear morphology, to histological images of haematoxylin and eosin-stained breast biopsy samples from healthy female donors at the Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (Indianapolis, IN, USA). All KTB participants (aged ≥18 years) who underwent core biopsies for research purposes between 2009 and 2019 were eligible for the study. Senescence was predicted in the epithelial (terminal duct lobular units [TDLUs] and non-TDLU epithelium), stromal, and adipose tissue compartments using validated models, previously trained on cells induced to senescence by ionising radiation (IR), replicative exhaustion (or replicative senescence; RS), or antimycin A, atazanavir-ritonavir, and doxorubicin (AAD) exposures. To benchmark our senescence-based cancer prediction results, we generated 5-year Gail scores-the current clinical gold standard for breast cancer risk prediction-for participants aged 35 years and older on the basis of characteristics at the time of tissue donation. The primary outcome was estimated odds of breast cancer via logistic modelling for each tissue compartment based on predicted senescence scores in cases (participants who had been diagnosed with breast cancer as of data cutoff, July 31, 2022) and controls (those who had not been diagnosed with breast cancer). 4382 female donors (median age at donation 45 years [IQR 34-57]) were eligible for the study. As of data cutoff (median follow-up of 10 years [7-11]), 86 (2·0%) had developed breast cancer a mean of 4·8 years (SD 2·84) after date of donation and 4296 (98·0%) had not received a breast cancer diagnosis. Among the 86 cases, we found significant differences in adipose-specific IR and AAD senescence prediction scores compared with controls. Risk analysis showed that individuals in the upper half (above the median) of scores for the adipose tissue IR model had higher odds of developing breast cancer (odds ratio [OR] 1·71 [95% CI 1·10-2·68]; p=0·019), whereas the adipose AAD model revealed a reduced odds of developing breast cancer (OR 0·57 [0·36-0·88]; p=0·013). For the other tissue compartments and the RS model, no significant associations were found (except for stromal tissue via the IR model, had higher odds of developing breast cancer [OR 1·59, 1·03-2·49]). Individuals with both of the adipose risk factors had an OR of 3·32 (1·68-7·03; p=0·0009). Participants with 5-year Gail scores above the median had an OR for development of cancer of 2·33 (1·46-3·82; p=0·0012) compared with those with scores below the median. When combining Gail scores with our adipose AAD risk model, we found that individuals with both of these predictors had an OR of 4·70 (2·29-10·90; p<0·0001). When combining the Gail score with our adipose IR model, we found that individuals with both predictors had an OR of 3·45 (1·77-7·24; p=0·0002). Assessment of senescence-associated nuclear morphologies with deep learning allows prediction of future cancer risk from normal breast biopsy samples. The combination of multiple models improved prediction of future breast cancer compared with the current clinical benchmark, the Gail model. Our results suggest an important role for microscope image-based deep learning models in predicting future cancer development. Such models could be incorporated into current breast cancer risk assessment and screening protocols. Novo Nordisk Foundation, Danish Cancer Society, and the US National Institutes of Health.

Female-to-male allogeneic transplantation affects outcomes differently according to the type of haplo-transplantation

Allogeneic hematopoietic stem cell transplantation from a female donor to a male recipient (female-to-male allo-HCT) is a well-established risk factor for chronic graft-versus-host disease (GVHD) and non-relapse mortality (NRM). The inferior outcomes of female-to-male allo-HCT are considered to be due to allo-immunity against H-Y antigens. However, the influence of minor histocompatibility antigens in haplo-identical allo-HCT remains to be elucidated. We investigated the impact of female-to-male allo-HCT according to the haplo-HCT subtype. In the post-transplant cyclophosphamide (PTCY) cohort (n = 660), a female-to-male sex-mismatch was significantly associated with a decreased risk of relapse (HR: 0.70 [95% CI: 0.49–0.99], P = 0.045), but not with overall survival (OS) or NRM (HR: OS 0.89 [95% CI: 0.68–1.16], P = 0.40; NRM 0.98 [95% CI: 0.68–1.41], P = 0.90). On the other hand, in the non-PTCY cohort (n = 219), a female-to-male sex-mismatch was associated with inferior risks of OS and NRM, but was not associated with relapse. These results suggested that the survival impact of the haplo-HCT subtype differed according to the presence of a sex-mismatch. PTCY might be feasible for overcoming the inferiority of female-to-male allo-HCT and might preserve a GVL effect against H-Y antigens.

Long-term outcome of 2-year survivors after allogeneic hematopoietic cell transplantation for acute leukemia.

Information on late complications in patients with acute leukemia who have undergone allogeneic hematopoietic cell transplantation (HCT) is limited. We performed a left-truncated analysis of long-term survival in patients with acute leukemia who were alive and disease-free 2 years after HCT. We included 2701 patients with acute lymphoblastic leukemia (ALL) and 9027 patients with acute myeloid leukemia (AML) who underwent HCT between 2005 and 2012. The 10-year overall survival (OS) rate was 81.3% for ALL and 76.2% for AML, with the main causes of late mortality being relapse (ALL-33.9%, AML-44.9%) and chronic graft-versus-host disease (ALL-29%, AML-18%). At 10 years, HCT-related mortality was 16.8% and 20.4%, respectively. Older age and unrelated donor transplantation were associated with a worse prognosis for both types of leukemia. In addition, transplantation in the second or third complete remission and peripheral blood HSC for ALL are associated with worse outcomes. Similarly, adverse cytogenetics, female donor to male patient combination, and reduced intensity conditioning in AML contribute to poor prognosis. We conclude that 2-year survival in remission after HCT for acute leukemia is encouraging, with OS of nearly 80% at 10 years. However, the long-term mortality risk of HCT survivors remains significantly higher than that of the age-matched general population. These findings underscore the importance of tailoring transplantation strategies to improve long-term outcomes in patients with acute leukemia undergoing HCT.

Understanding Blood Donation Practices in Gilgit, Pakistan An Anthropological Perspective

Blood is widely recognized as an essential bodily fluid crucial for sustaining life, and blood donation plays a critical role in saving lives. Ensuring access to a safe and sufficient supply of blood and its derivatives and reliable blood transfusion services is indispensable for a strong healthcare system. It is important to note that voluntary non-remunerated blood donors are the most reliable source of safe blood supply. In Pakistan, 70% of donated blood comes from replacement or paid donations, while only 10% comes from voluntary donations. In Gilgit, voluntary blood donation is scarce, and most blood comes from replacements. The respondents display limited understanding of blood transfusion, while they exhibit a positive attitude toward voluntary blood donation despite low participation. This discrepancy is attributed to inadequate awareness and campaigns, as well as prevalent myths and negative perceptions associated with blood and blood donation. Furthermore, sectarian-based segregation, the symbolic relationships between the donor and recipient and the exclusion of female blood donors exacerbate the gap between blood supply and demand. The research emphasises culturally suited solutions and strategies that can help enhance voluntary blood donation in Gilgit.

Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence.

Beta (β)-cell senescence contributes to type 2 diabetes mellitus (T2DM). While exercise is vital for T2DM management and significantly affects cellular ageing markers, its effect on β-cell senescence remains unexplored. Here, we show that short-term endurance exercise training (treadmill running, 1 h per day for 10 days) in two male and female mouse models of insulin resistance decreases β-cell senescence. In vivo and in vitro experiments revealed that this effect is mediated, at least in part, by training-induced increases in serum glucagon, leading to activation of 5'-AMP-activated protein kinase (AMPK) signalling in β-cells. AMPK activation resulted in the nuclear translocation of NRF2 and decreased expression of senescence markers and effectors. Remarkably, human islets from male and female donors with T2DM treated with serum collected after a 10-week endurance exercise training programme showed a significant decrease in the levels of senescence markers. These findings indicate that exercise training decreases senescence in pancreatic islets, offering promising therapeutic implications for T2DM.