Testing for t(3;8) in MYC/BCL6-rearranged large B-cell lymphoma identifies a high-risk subgroup with inferior survival.

ABSTRACT: A reciprocal t(3;8) BCL6::MYC fusion is common in large B-cell lymphoma (LBCL) with MYC and BCL6 disruption. These pseudo-double-hit cases are not adverse, whereas t(3;8)-MYC/BCL6 lymphoma has an inferior prognosis relative to other MYC-rearranged LBCL.

Ibrutinib for mantle cell lymphoma at first relapse: a United Kingdom real-world analysis of outcomes in 211 patients.

Ibrutinib is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL) and clinical trial data supports use at second line compared to later relapse. We aimed to investigate outcomes and tolerability for ibrutinib when given second line in a real-world setting. Our multicentre retrospective analysis included 211 R/R MCL patients, median age 73 years, receiving ibrutinib second-line within the United Kingdom's National Health Service. Overall response to ibrutinib was 69% (complete response 27%). The median progression-free survival (PFS) was 17·8 months (95% CI 13·1-22·2) and median overall survival (OS) 23·9 months (95% CI 15·0-32·8). Drug-related adverse event led to dose reduction in 10% of patients and discontinuation in 5%. In patients with progressive disease, accounting for 100 of 152 patients stopping ibrutinib, 43% received further systemic therapy. Post-ibrutinib rituximab, bendamustine and cytarabine (R-BAC) showed a trend toward improved survival compared to alternative systemic treatments (post-ibrutinib median OS 14·0 months, 95% CI 8·1-19·8, vs. 3·6 months, 95% CI 2·6-4·5, P = 0·06). Our study confirms the clinical benefit and good tolerability of ibrutinib at first relapse in a real-world population. Patients progressing on ibrutinib had limited survival but outcomes with R-BAC in select patients were promising.

Efficacy of R-BAC in relapsed, refractory mantle cell lymphoma post BTK inhibitor therapy.

Patients with mantle cell lymphoma progressing on Bruton's tyrosine kinase inhibitor (BTKi) have very poor prognosis and there is currently no standard of care. In this retrospective cohort study, patients progressing on BTKi received R-BAC (rituximab, bendamustine, cytarabine). Overall response rate was 83% (complete response 60%) and 31% were bridged to allogeneic stem cell transplant (alloSCT). Median progression-free survival was 10.1 months (95% confidence interval (CI) 6·9-13·3) and median overall survival was 12·5 months (95% CI 11·0-14·0). In those consolidated with alloSCT only one patient relapsed. R-BAC demonstrates a high response rate in the post-BTKi setting and in transplant eligible patients is an effective bridge to alloSCT.

Imaging mass spectrometry enables molecular profiling of mouse and human pancreatic tissue.

AIMS/HYPOTHESIS: The molecular response and function of pancreatic islet cells during metabolic stress is a complex process. The anatomical location and small size of pancreatic islets coupled with current methodological limitations have prevented the achievement of a complete, coherent picture of the role that lipids and proteins play in cellular processes under normal conditions and in diseased states. Herein, we describe the development of untargeted tissue imaging mass spectrometry (IMS) technologies for the study of in situ protein and, more specifically, lipid distributions in murine and human pancreases. METHODS: We developed matrix-assisted laser desorption/ionisation (MALDI) IMS protocols to study metabolite, lipid and protein distributions in mouse (wild-type and ob/ob mouse models) and human pancreases. IMS allows for the facile discrimination of chemically similar lipid and metabolite isoforms that cannot be distinguished using standard immunohistochemical techniques. Co-registration of MS images with immunofluorescence images acquired from serial tissue sections allowed accurate cross-registration of cell types. By acquiring immunofluorescence images first, this serial section approach guides targeted high spatial resolution IMS analyses (down to 15 µm) of regions of interest and leads to reduced time requirements for data acquisition. RESULTS: MALDI IMS enabled the molecular identification of specific phospholipid and glycolipid isoforms in pancreatic islets with intra-islet spatial resolution. This technology shows that subtle differences in the chemical structure of phospholipids can dramatically affect their distribution patterns and, presumably, cellular function within the islet and exocrine compartments of the pancreas (e.g. 18:1 vs 18:2 fatty acyl groups in phosphatidylcholine lipids). We also observed the localisation of specific GM3 ganglioside lipids [GM3(d34:1), GM3(d36:1), GM3(d38:1) and GM3(d40:1)] within murine islet cells that were correlated with a higher level of GM3 synthase as verified by immunostaining. However, in human pancreas, GM3 gangliosides were equally distributed in both the endocrine and exocrine tissue, with only one GM3 isoform showing islet-specific localisation. CONCLUSIONS/INTERPRETATION: The development of more complete molecular profiles of pancreatic tissue will provide important insight into the molecular state of the pancreas during islet development, normal function, and diseased states. For example, this study demonstrates that these results can provide novel insight into the potential signalling mechanisms involving phospholipids and glycolipids that would be difficult to detect by targeted methods, and can help raise new hypotheses about the types of physiological control exerted on endocrine hormone-producing cells in islets. Importantly, the in situ measurements afforded by IMS do not require a priori knowledge of molecules of interest and are not susceptible to the limitations of immunohistochemistry, providing the opportunity for novel biomarker discovery. Notably, the presence of multiple GM3 isoforms in mouse islets and the differential localisation of lipids in human tissue underscore the important role these molecules play in regulating insulin modulation and suggest species, organ, and cell specificity. This approach demonstrates the importance of both high spatial resolution and high molecular specificity to accurately survey the molecular composition of complex, multi-functional tissues such as the pancreas.

Neuromorphic Liquid Marbles with Aqueous Carbon Nanotube Cores.

Neuromorphic computing devices attempt to emulate features of biological nervous systems through mimicking the properties of synapses toward implementing the emergent properties of their counterparts, such as learning. Inspired by recent advances in the utilization of liquid marbles (LMs, microliter quantities of fluid coated in hydrophobic powder) for the creation of unconventional computing devices, we describe the development of LMs with neuromorphic properties through the use of copper coatings and 1.0 mg mL-1 carbon nanotube (CNT)-containing fluid cores. Experimentation was performed through sandwiching the LMs between two cup-style electrodes and stimulating them with repeated dc pulses at 3.0 V. Our results demonstrate that "entrainment" of CNT-filled copper LMs via periodic pulses can cause their electrical resistance to rapidly switch between high to low resistance profiles upon inverting the polarity of stimulation: the reduction in resistance between high and low profiles was approximately 88% after two rounds of entrainment. This effect was found to be reversible through reversion to the original stimulus polarity and was strengthened by repeated experimentation, as evidenced by a mean reduction in time to switching onset of 43%. These effects were not replicated in nanotube solutions not bound inside LMs. Our electrical characterization also reveals that nanotube-filled LMs exhibit pinched loop hysteresis IV profiles consistent with the description of memristors. We conclude by discussing the applications of this technology to the development of unconventional computing devices and the study of emergent characteristics in biological neural tissue.

Mapping outcomes of liquid marble collisions.

Liquid marbles (LMs) have many promising roles in the ongoing development of microfluidics, microreactors, bioreactors, and unconventional computing. In many of these applications, the coalescence of two LMs is either required or actively discouraged, therefore it is important to study liquid marble collisions and establish parameters which enable the desired collision outcome. Recent reports on LM coalescence have focused on either two mobile LMs colliding, or an accelerating LM hitting a sessile LM with a backstop. A further possible scenario is the impact of a mobile LM against a non-supported static LM. This paper investigates such a collision, using high-speed videography for single-frame analysis. Multiple collisions were undertaken whilst varying the modified Weber number (We*) and offset ratios (X*). Parameter ranges of 1.0 < We* < 1.4 and 0.0 < X* < 0.1, resulted in a coalescence rate of approximately 50%. Whereas, parameter ranges X* > 0.25, and We* < 0.95 or We* > 1.55 resulted in 100% non-coalescence. Additionally, observations of LMs moving above a threshold velocity of 0.6 m s-1 have revealed a new and unusual deformation. Comparisons of the outcome of collisions whilst varying both the LM volume and the powder grain size have also been made, revealing a strong link. The results of this work provide a deeper understanding of LM coalescence, allowing improved control when designing future collision experiments.

Evaporation, Lifetime, and Robustness Studies of Liquid Marbles for Collision-Based Computing.

Liquid marbles (LMs) have recently attracted interest for use as cargo carriers in digital microfluidics and have successfully been implemented as signal carriers in collision-based unconventional computing circuits. Both application domains require LMs to roll over substantial distances and to survive a certain number of collisions without degrading. To evaluate the lifetime of LMs being subjected to movement and impact stresses, we have selected four types of coating to investigate: polytetrafluoroethylene (PTFE), ultrahigh density polyethylene (PE), Ni, and a mixture of Ni with PE (Ni-PE). Hierarchies of robustness have been constructed which showed that pure PE LMs survived the longest when stationary and in motion. Pure PTFE LMs were shown to be the least resilient to multiple impacts. The PTFE coating provided minimal protection against evaporative losses for small LM volumes (2 and 5 µL) however, larger LMs (10 µL) were shown to have good evaporative stabilities when stationary. Conversely, PE LMs showed a remarkable ability to withstand multiple impacts and were also stable when considering just passive evaporation. Hybrid Ni-PE LMs exhibited more resilience to multiple impacts compared to Ni LMs. Thus, when designing LM devices, it is paramount to determine impact pathways and select appropriate coating materials.

Protection of intestinal injury during heat stroke in mice by interleukin-6 pretreatment.

KEY POINTS: Heat stroke afflicts thousands of humans each year, worldwide. The immune system responds to hyperthermia exposure resulting in heat stroke by producing an array of immunological proteins, such as interleukin-6 (IL-6). However, the physiological functions of IL-6 and other cytokines in hyperthermia are poorly understood. We hypothesized that IL-6 plays a protective role in conditions of heat stroke. To test this, we gave small IL-6 supplements to mice prior to exposing them to hot environments sufficient to induce conditions of heat stroke. Pretreatment with IL-6 resulted in improved ability to withstand heat exposure in anaesthetized mice, it protected the intestine from injury, reducing the permeability of the intestinal barrier, and it attenuated the release of other cytokines involved in inflammation. The results support the hypothesis that IL-6 is a 'physiological stress hormone' that plays an important role in survival during acute life-threatening conditions such as heat stroke. ABSTRACT: The role of interleukin-6 (IL-6) in hyperthermia and heat stroke is poorly understood. Plasma IL-6 is elevated following hyperthermia in animals and humans, and IL-6 knockout mice are more intolerant of severe hyperthermia. We evaluated the effect of IL-6 supplementation on organ injury following severe hyperthermia exposure in anaesthetized mice. Two hours prior to hyperthermia, mice were treated with 0.6 µg intraperitoneal IL-6, or identical volumes of saline in controls. Mice were anaesthetized, gavaged with FITC-dextran for measures of gastrointestinal permeability, and exposed to incremental (0.5°C every 30 min) increases in temperature. Heating stopped when maximum core temperature (Tc) of 42.4°C was attained (Tc,max). The mice recovered at room temperature (≈22°C) for 30 or 120 min, at which time plasma and tissues were collected. IL-6-treated mice, on average, required ≈25 min longer to attain Tc,max . Injury and swelling of the villi in the duodenum was present in untreated mice after 30 min of recovery. These changes were blocked by IL-6 treatment. IL-6 also reduced gastrointestinal permeability, assayed by the accumulation of FITC-dextran in plasma. Plasma cytokines were also attenuated in IL-6-treated animals, including significant reductions in TNFα, MCP-1 (CXCL2), RANTES (CCL5) and KC (CCL5). The results demonstrate that IL-6 has a protective influence on the pattern of physiological responses to severe hyperthermia, suggesting that early endogenous expression of IL-6 may provide a protection from the development of organ damage and inflammation.

Ibrutinib as first-line therapy for mantle cell lymphoma: a multicenter, real-world UK study.

ABSTRACT: During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.

Regional susceptibility to stress-induced intestinal injury in the mouse.

Injury to the intestinal mucosa is a life-threatening problem in a variety of clinical disorders, including hemorrhagic shock, trauma, burn, pancreatitis, and heat stroke. The susceptibility to injury of different regions of intestine in these disorders is not well understood. We compared histological injury across the small intestine in two in vivo mouse models of injury, hemorrhagic shock (30% loss of blood volume) and heat stroke (peak core temperature 42.4°C). In both injury models, areas near the duodenum showed significantly greater mucosal injury and reductions in villus height. To determine if these effects were dependent on circulating factors, experiments were performed on isolated intestinal segments to test for permeability to 4-kDa FITC-dextran. The segments were exposed to hyperthermia (42°C for 90 min), moderate simulated ischemia (Po2 ∼30 Torr, Pco2 ∼60 Torr, pH 7.1), severe ischemia (Po2 ∼20 Torr, Pco2 ∼80 Torr, pH 6.9), or severe hypoxia (Po2 ∼0 Torr, Pco2 ∼35 Torr) for 90 min, and each group was compared with sham controls. All treatments resulted in marked elevations in permeability within segments near the duodenum. In severe hypoxia or hyperthermia, permeability was also moderately elevated in the jejunum and ileum; in moderate or severe ischemia, permeability was unaffected in these regions. The results demonstrate increased susceptibility of proximal regions of the small intestine to acute stress-induced damage, irrespective of circulating factors. The predominant injury in the duodenum may impact the pattern of acute inflammatory responses arising from breach of the intestinal barrier, and such knowledge may be useful for designing therapeutic strategies.

Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells.

Human embryonic stem cells (hESCs) can serve as a universal cell source for emerging cell or tissue replacement strategies, but immune rejection of hESC derivatives remains an unsolved problem. Here, we sought to describe the mechanisms of rejection for naïve hESCs and upon HLA class I (HLA I) knockdown (hESC(KD)). hESCs were HLA I-positive but negative for HLA II and co-stimulatory molecules. Transplantation of naïve hESC into immunocompetent Balb/c mice induced substantial T helper cell 1 and 2 (Th1 and Th2) responses with rapid cell death, but hESCs survived in immunodeficient SCID-beige recipients. Histology revealed mainly macrophages and T cells, but only scattered natural killer (NK) cells. A surge of hESC-specific antibodies against hESC class I, but not class II antigens, was observed. Using HLA I RNA interference and intrabody technology, HLA I surface expression of hESC(KD) was 88%-99% reduced. T cell activation after hESC(KD) transplantation into Balb/c was significantly diminished, antibody production was substantially alleviated, the levels of graft-infiltrating immune cells were reduced and the survival of hESC(KD) was prolonged. Because of their very low expression of stimulatory NK ligands, NK-susceptibility of naïve hESCs and hESC(KD) was negligible. Thus, HLA I recognition by T cells seems to be the primary mechanism of hESC recognition, and T cells, macrophages and hESC-specific antibodies participate in hESC killing.

Electrical response of fungi to changing moisture content.

Mycelium-bound composites are potential alternatives to conventional materials for a variety of applications, including thermal and acoustic building panels and product packaging. If the reactions of live mycelium to environmental conditions and stimuli are taken into account, it is possible to create functioning fungal materials. Thus, active building components, sensory wearables, etc. might be created. This research describes the electrical sensitivity of fungus to changes in the moisture content of a mycelium-bound composite. Trains of electrical spikes initiate spontaneously in fresh mycelium-bound composites with a moisture content between [Formula: see text] 95% and [Formula: see text] 65%, and between [Formula: see text] 15% and [Formula: see text] 5% when partially dried. When the surfaces of mycelium-bound composites were partially or totally encased with an impermeable layer, increased electrical activity was observed. In fresh mycelium-bound composites, electrical spikes were seen both spontaneously and when induced by water droplets on the surface. Also explored is the link between electrical activity and electrode depth. Future designs of smart buildings, wearables, fungi-based sensors, and unconventional computer systems may benefit from fungi configurations and biofabrication flexibility.

Transfer functions of proteinoid microspheres.

Proteinoids, or thermal proteins, are inorganic entities formed by heating amino acids to their melting point and commencing polymerisation to form polymeric chains. Typically, their diameters range from 1µm to 10µm. Some amino acids incorporated into proteinoid chains are more hydrophobic than others, leading proteinoids to cluster together when they are present in aqueous solutions at specific concentrations, allowing them to grow into microspheres. The peculiar structure of proteinoids composed of linked amino acids endows them with unique properties, including action-potential like spiking of electrical potential. These unique properties make ensembles of proteinoid microspheres a promising substrate for designing future artificial brains and unconventional computing devices. To evaluate a potential of proteinoid microspheres for unconventional electronic devices we measure and analyse the data-transfer capacities of proteinoid microspheres. In experimental laboratory conditions we demonstrate that the transfer function of proteinoids microspheres is a nontrivial phenomenon, which might be due to the wide range of proteinoid shapes, sizes, and structures.

Responsive fungal insoles for pressure detection.

Mycelium bound composites are promising materials for a diverse range of applications including wearables and building elements. Their functionality surpasses some of the capabilities of traditionally passive materials, such as synthetic fibres, reconstituted cellulose fibres and natural fibres. Thereby, creating novel propositions including augmented functionality (sensory) and aesthetic (personal fashion). Biomaterials can offer multiple modal sensing capability such as mechanical loading (compressive and tensile) and moisture content. To assess the sensing potential of fungal insoles we undertook laboratory experiments on electrical response of bespoke insoles made from capillary matting colonised with oyster fungi Pleurotus ostreatus to compressive stress which mimics human loading when standing and walking. We have shown changes in electrical activity with compressive loading. The results advance the development of intelligent sensing insoles which are a building block towards more generic reactive fungal wearables. Using FitzHugh-Nagumo model we numerically illustrated how excitation wave-fronts behave in a mycelium network colonising an insole and shown that it may be possible to discern pressure points from the mycelium electrical activity.

Propagation of electrical signals by fungi.

Living fungal mycelium networks are proven to have properties of memristors, capacitors and various sensors. To further progress our designs in fungal electronics we need to evaluate how electrical signals can be propagated through mycelium networks. We investigate the ability of mycelium-bound composites to convey electrical signals, thereby enabling the transmission of frequency-modulated information. Mycelium networks were found to reliably transfer signals with a recoverable frequency comparable to the input, in the 100Hz to 10 000Hz frequency range. Mycelial adaptive responses, such as tissue repair, may result in fragile connections, however. While the mean amplitude of output signals was not reproducible among replicate experiments exposed to the same input frequency, the variance across groups was highly consistent. Our work is supported by NARX modelling through which an approximate transfer function was derived. These findings advance the state of the art of using mycelium-bound composites in analogue electronics and unconventional computing.

No ultrasounds detected from fungi when dehydrated.

Many organisms (including certain plant species) can be observed to emit sounds, potentially signifying threat alerts. Sensitivity to such sounds and vibrations may also play an important role in the lives of fungi. In this work, we explore the potential of ultrasound activity in dehydrating fungi, and discover that several species of fungi do not emit sounds (detectable with conventional instrumentation) in the frequency range of 10kHz to 210kHz upon dehydration. Over 5 terabytes of ultrasound recordings were collected and analysed. We conjecture that fungi interact via non-sound means, such as electrical or chemical.

Kombucha electronics: electronic circuits on kombucha mats.

A kombucha is a tea and sugar fermented by over sixty kinds of yeasts and bacteria. This symbiotic community produces kombucha mats, which are cellulose-based hydrogels. The kombucha mats can be used as an alternative to animal leather in industry and fashion once they have been dried and cured. Prior to this study, we demonstrated that living kombucha mats display dynamic electrical activity and distinct stimulating responses. For use in organic textiles, cured mats of kombucha are inert. To make kombucha wearables functional, it is necessary to incorporate electrical circuits. We demonstrate that creating electrical conductors on kombucha mats is possible. After repeated bending and stretching, the circuits maintain their functionality. In addition, the abilities and electronic properties of the proposed kombucha, such as being lighter, less expensive, and more flexible than conventional electronic systems, pave the way for their use in a diverse range of applications.

Hyperthermia increases interleukin-6 in mouse skeletal muscle.

Skeletal muscles produce and contribute to circulating levels of IL-6 during exercise. However, when core temperature is reduced, the response is attenuated. Therefore, we hypothesized that hyperthermia may be an important and independent stimulus for muscle IL-6. In cultured C2C12 myotubes, hyperthermia (42°C) increased IL-6 gene expression 14-fold after 1 h and 35-fold after 5 h of 37°C recovery; whereas exposure to 41°C resulted in a 2.6-fold elevation at 1 h. IL-6 protein was secreted and significantly elevated in the cell supernatant. Similar but reduced responses to heat were seen in C2C12 myoblasts. Isolated soleus muscles from mice, exposed ex vivo to 41°C for 1 h, yielded similar IL-6 gene responses (>3-fold) but without a significant effect on protein release. When whole animals were exposed to passive hyperthermia, such that core temperature increased to 42.4°C, IL-6 mRNA in soleus increased 5.4-fold compared with time matched controls. Interestingly, TNF-α gene expression was routinely suppressed at all levels of hyperthermia (40.5-42°C) in the isolated models, but TNF-α was elevated (4.2-fold) in the soleus taken from intact mice exposed, in vivo, to hyperthermia. Muscle HSP72 mRNA increased as a function of the level of hyperthermia, and IL-6 mRNA responses increased proportionally with HSP72. In cultured C2C12 myotubes, when heat shock factor was pharmacologically blocked with KNK437, both HSP72 and IL-6 mRNA elevations, induced by heat, were suppressed. These findings implicate skeletal muscle as a "heat stress sensor" at physiologically relevant hyperthermia, responding with a programmed cytokine expression pattern characterized by elevated IL-6.

Human leukocyte antigen I knockdown human embryonic stem cells induce host ignorance and achieve prolonged xenogeneic survival.

BACKGROUND: Although human embryonic stem cells (hESC) have enormous potential for cell replacement therapy of heart failure, immune rejection of hESC derivatives inevitably would occur after transplantation. We therefore aimed to generate a hypoantigeneic hESC line with improved survival characteristics. METHODS AND RESULTS: Using various in vivo, nonischemic, hindlimb xenotransplant models (immunocompetent and defined immunodefective mouse strains) as well as human in vitro T-cell and natural killer (NK)-cell assays, we revealed a central role for T cells in mediating hESC rejection. The NK-cell susceptibility of hESC in vivo was found to be low, and the NK response to hESC challenge in vitro was negligible. To reduce the antigenicity of hESC, we successfully generated human leukocyte antigen (HLA) I knockdown cells (hESC(siRNA+IB)) using both HLA I RNA interference (siRNA) and intrabody (IB) technology. HLA I expression was ≈99% reduced after 7 days and remained low for weeks. Cellular immune recognition of these hESC(siRNA+IB) was strongly reduced in both xenogeneic and allogeneic settings. Immune rejection was profoundly mitigated after hESC(siRNA+IB) transplantation into immunocompetent mice, and even long-term graft survival was achieved in one third of the animals without any immunosuppression. The survival benefit of hESC(siRNA+IB) was further confirmed under ischemic conditions in a left anterior descending coronary artery ligation model. CONCLUSIONS: HLA I knockdown hESC(siRNA+IB) provoke T-cell ignorance and experience largely mitigated xenogeneic rejection. By generating hypoantigeneic hESC lines, the generation of acceptable hESC derivatives may become a practical concept and push cell replacement strategies forward.