Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein functio...Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.展开更多
BACKGROUND Significant gaps in guideline-directed medical therapy(GDMT)for heart failure(HF)stem from shortages of cardiologists and advanced HF providers,as well as a lack of optimal HF management knowledge among hos...BACKGROUND Significant gaps in guideline-directed medical therapy(GDMT)for heart failure(HF)stem from shortages of cardiologists and advanced HF providers,as well as a lack of optimal HF management knowledge among hospitalists.This study compared the impact of optimal medical therapy in HF(OMT-HF)certification on GDMT implementation and patient outcomes between an intervention group(IG)of hospitalists and a standard-of-care comparison group(SOC-CG).METHODS This study was implemented from November 2022 to May 2023.Hospitalized car-diology patients with HF and left ventricular ejection fraction≤40%were rando-mized to IG or SOC-CG.Exclusion criteria included patients in cardiogenic shock,unable to consent,or at high risk.Follow-up was at 30 days post-discharge.Diffe-rences between groups were analyzed using Fisher’s exact test for categorical va-riables and Wilcoxon rank-sum or unpaired t-test for continuous variables.Chan-ges in Minnesota Living with Heart Failure Questionnaire(MLWHFQ)scores were evaluated using a paired t-test.RESULTS IG patients had lower readmission rates[9(42.85%)vs 11(17.46%),P=0.03]and a decreased trend in mortality 30-day post discharge.IG patients also showed greater mean improvements in total(-27.03±24.59 vs-5.85±23.52,P<0.001),physical(-13.8±12.3 vs-2.71±11.16,P<0.001)and emotional(-4.76±8.10 vs-1.42±5.98)dimensions on the MLWHFQ compared to SOC-CG,however,change in emotional dimension did not reach statistical significance.CONCLUSION Hospitalist OMT-HF certification may lead to better 30-day outcomes in hospitalized HF patients including quality of life,mortality and readmission rates.Larger prospective studies are warranted to validate these findings.展开更多
More recently, the biomedical applications of MnO2 in bioanalysis, cell imaging, and drug delivery as a result of their appealing physicochemical properties, have been reported and expanded rapidly. However, research ...More recently, the biomedical applications of MnO2 in bioanalysis, cell imaging, and drug delivery as a result of their appealing physicochemical properties, have been reported and expanded rapidly. However, research on a near infrared （NIR） photothermal response of MnO2 was ignored. In this work, we reported a facile, one-pot method to synthesis of bovine serum albumin （BSA）-reduced and stabilized MnO2 nanoparticles （BSA-MnO2 NPs） with good aqueous dispersibility and high biocompatibility. And we also showed for the first time that BSA-MnO2 NPs displayed superior NIR photothermal efficiency and photostability which demonstrated as a novel class of photothermal antitumor agent.展开更多
With appropriate stimuli,such as heat,humidity,or magnetic field,shape memory polymers(SMPs)can recover to their original shapes from temporary,programmed states.Using thermal responsive SMPs as substrates,we demonstr...With appropriate stimuli,such as heat,humidity,or magnetic field,shape memory polymers(SMPs)can recover to their original shapes from temporary,programmed states.Using thermal responsive SMPs as substrates,we demonstrate a simple method to realize hybrid surface morphologies through confined thin film wrinkling in localized areas.The bilayer system was fabricated by depositing a layer of aluminum thin?lm on top of a SMP substrate programmed with a tensile strain.After the system was heated by a heating wire,hybrid wrinkling patterns were formed in a confined circular area around the heat source,with an inner spoke pattern and an outer ring pattern.Wrinkling patterns showed good symmetry,and the size of the wrinkling area can be tuned by controlling the heat input.This study o?ers a simple but effective approach to fabricate hybrid morphological features in micro-scale.With appropriate stimuli,such as heat,humidity,or magnetic field,shape memory polymers(SMPs)can recover to their original shapes from temporary,programmed states.Using thermal responsive SMPs as substrates,we demonstrate a simple method to realize hybrid surface morphologies through confined thin film wrinkling in localized areas.The bilayer system was fabricated by depositing a layer of aluminum thin?lm on top of a SMP substrate programmed with a tensile strain.After the system was heated by a heating wire,hybrid wrinkling patterns were formed in a confined circular area around the heat source,with an inner spoke pattern and an outer ring pattern.Wrinkling patterns showed good symmetry,and the size of the wrinkling area can be tuned by controlling the heat input.This study offers a simple but effective approach to fabricate hybrid morphological features in micro-scale.展开更多
Convection-enhanced delivery （CED） is a promising technique leveraging pressure-driven flow to increase penetration of infused drugs into interstitial spaces. We have developed a fiberoptic microneedle device for in...Convection-enhanced delivery （CED） is a promising technique leveraging pressure-driven flow to increase penetration of infused drugs into interstitial spaces. We have developed a fiberoptic microneedle device for inducing local sub-lethal hyperthermia to further improve CED drug distribution volumes, and this study seeks to quantitatively characterize this approach in agarose tissue phantoms. Infusions of dye were conducted in 0.6% （w/w） agarose tissue phantoms with isothermal conditions at 15 ℃, 20℃, 25 ℃, and 30 ℃. Infusion metrics were quantified using a custom shadowgraphy setup and image- processing algorithm. These data were used to build an empirical predictive temporal model of distribution volume as a function of phantom temperature. A second set of proof- of-concept experiments was conducted to evaluate a novel fiberoptic device capable of generating local photothermal heating during fluid infusion. The isothermal infusions showed a positive correlation between temperature and distribution volume, with the volume at 30℃ showing a 7-fold increase at 100 min over the 15 ℃ isothermal case. Infusions during photothermal heating （1064 nm at 500 mW） showed a similar effect with a 3.5-fold increase at 4 h over the control （0 mW）. These results and analyses serve to provide insight into and characterization of heat-mediated enhancement of volumetric dispersal.展开更多
B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known a...B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial–mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.展开更多
The high demand for lung transplants cannot be matched by an adequate number of lungs from donors. Since fully ex-novo lungs are far from being feasible, tissue engineering is actively considering implantation of engi...The high demand for lung transplants cannot be matched by an adequate number of lungs from donors. Since fully ex-novo lungs are far from being feasible, tissue engineering is actively considering implantation of engineered lungs where the devitalized structure of a donor is used as scaffold to be repopulated by stem cells of the receiving patient. A decellularized donated lung is treated inside a bioreactor where transport through the tracheobronchial tree (TBT) will allow for both deposition of stem cells and nourishment for their subsequent growth, thus developing new lung tissue. The key concern is to set optimally the boundary conditions to utilize in the bioreactor. We propose a predictive model of slow liquid ventilation, which combines a one-dimensional (1-D) mathematical model of the TBT and a solute deposition model strongly dependent on fluid velocity across the tree. With it, we were able to track and drive the concentration of a generic solute across the airways, looking for its optimal distribution. This was given by properly adjusting the pumps’ regime serving the bioreactor. A feedback system, created by coupling the two models, allowed us to derive the optimal pattern. The TBT model can be easily invertible, thus yielding a straightforward flow/pressure law at the inlet to optimize the efficiency of the bioreactor.展开更多
BACKGROUND The impact of pancreatic tumor location on patient survival has been studied in large national data-based analyses which yielded controversial results.AIM To explore if pancreatic head cancer(PHC)and pancre...BACKGROUND The impact of pancreatic tumor location on patient survival has been studied in large national data-based analyses which yielded controversial results.AIM To explore if pancreatic head cancer(PHC)and pancreatic body/tail cancer(PBTC)have different overall survival(OS),molecular signature and response to chemotherapy.METHODS We retrospectively queried patient records from July 2016 to June 2020 in our institution.Patient demographics,cancer stage on diagnosis,tumor location,somatic mutations,treatment,and survival are recorded and analyzed.A test is considered statistically significant if the P value was<0.05.RESULTS We reviewed 101 patients with complete records,among which 67(66.34%)were PHC and 34(33.66%)were PBTC.More PHC were diagnosed at younger age[61.49 vs 68.97,P=0.010],earlier stages(P=0.006)and underwent surgical resection(P=0.025).There were no significant differences among all mutations and pathways studied except for TP53 mutations(37.0%in PHC vs 70.0%in PBTC,P=0.03).OS was not statistically different between PHC and PBTC(P=0.636)in the overall population and in subgroups according to surgical resection status or stages.In terms of response to chemotherapy,chemotherapy regimens(FOLFIRINOX-based vs gemcitabine-based)didn’t impact disease free interval in those who had surgical resection in either PHC(P=0.546)or PBTC(P=0.654),or the duration of response to first line palliative treatment in those with advanced disease in PHC(P=0.915)or PBTC(P=0.524).CONCLUSION Even though PHC and PBTC have similar poor OS and response to chemotherapy,the different presentations and molecular profiles indicate they are different diseases.Utilization of molecular profiling to develop targeted therapy for individualization of treatment is needed.展开更多
BACKGROUND Colorectal cancer(CRC)is the third leading cause of cancer-related death in males and females in the United States.Approximately,20%-22%of patients have metastatic disease at the time of presentation,and 50...BACKGROUND Colorectal cancer(CRC)is the third leading cause of cancer-related death in males and females in the United States.Approximately,20%-22%of patients have metastatic disease at the time of presentation,and 50%-60%will develop metastasis over the course of their disease.Despite advances in systemic therapies,there remains a paucity of effective third-and later-line therapies for patients with ongoing disease progression.However,rechallenging chemoresistant CRC tumors with previously administered therapies is an emerging concept that may be a life-prolonging option for heavily treated metastatic colorectal cancer(mCRC).CASE SUMMARY A 41-year-old man with no previous medical history initially presented with worsening diffuse abdominal tenderness.Computed tomography was significant for a splenic flexure mass and hepatic lesions concerning for metastatic disease.He underwent a colectomy with anastomosis.Postoperative pathology was diagnostic for moderately to well-differentiated adenocarcinoma(T4bN1bM1a).He received adjuvant 5-fluorouracil,leucovorin,and oxaliplatin(FOLFOX),but therapy was discontinued due to the development of atrial fibrillation.Additional workup indicated a carcinoembryonic antigen level of 508.2 ng/mL,and mutational analysis found that the tumor was microsatellite instability-high and KRAS/BRAF wild-type.He was started on irinotecan with oxaliplatin(IROX),and bevacizumab(14 cycles),developed disease progression,was transitioned to FOLFOX and cetuximab,and then eventually three cycles of pembrolizumab.Following disease progression,he was rechallenged with IROX therapy,as he previously responded well to oxaliplatin-based therapy.The IROX rechallenge provided this patient with a ten-month survival benefit,decreased metastatic burden,and marked improvement in his clinical condition.CONCLUSION Rechallenge of previous lines of well-tolerated systemic chemotherapy regimens may be a valuable therapeutic strategy in patients with heavily-treated mCRC.展开更多
Decades of biochemical studies have advanced DNA beyond its primary role as genetic blueprint.DNAzymes are single-stranded enzymatic DNA molecules that do not exist in nature.They are ideal candidates for gene silenci...Decades of biochemical studies have advanced DNA beyond its primary role as genetic blueprint.DNAzymes are single-stranded enzymatic DNA molecules that do not exist in nature.They are ideal candidates for gene silencing owing to their scalability by solid-phase synthesis(without batch variations),reprogrammability by directed evolution and local sequence alterations,compatibility with diverse delivery methods,and capability of achieving high catalytic turnover independent of any auxiliary proteins.With these unique features,various artificially evolved DNAzymes have been employed as theranostic tools in designing biosensors and logic gates,RNA/DNA cleavage and ligation,phosphorylation and dephosphorylation,DNA photorepair,and peptide side-chain modifications,to name but a few(Ponce-Salvatierra et al.,2021).This perspective will focus on the functional aspects and therapeutic potentials of RNA-cleaving DNAzymes.展开更多
Objectives: To demonstrate in vitro that changes in ultrasound cavitation threshold might be used for non-invasively distinguishing high viscosity mucinous fluid from low viscosity serous fluid in cystic masses, based...Objectives: To demonstrate in vitro that changes in ultrasound cavitation threshold might be used for non-invasively distinguishing high viscosity mucinous fluid from low viscosity serous fluid in cystic masses, based on the facts that cavitation threshold increases with increasing viscosity and that cavitation microbubbles are observable with diagnostic ultrasound. Methods: An in vitro model of a cyst was designed using dilutions of ultrasonic gel, and the cavitation threshold of this model was determined using focused and unfocused ultrasound for bubble initiation and clinical ultrasound b-scan for detection. Results: Viscosities of dilutions between 0% and 30% gel were had viscosities measuring between 1.05 ± 0.08 cP and 6600 ± 875 cP. Inertial cavitation in the latter was determined to require an order of magnitude greater intensity, at 1 MHz and 100% duty cycle, than the former (>2.2 W/cm2 vs. <0.19 W/cm2) using unfocused ultrasound. A four-fold increase in the peak negative pressure was required to initiate significant bubble activity using 1.1 MHz and 50% duty cycle focused ultrasound in the 6600 cP fluid compared with the 1 cP fluid. Based on these results, it was estimated that a threshold could be defined that would result in no bubbles in 99.9% of mucinous cysts and just 22% of serous cysts. The remaining 78% of patients presenting with serous cysts would be positively identified by detection of bubbles, and would be spared an unnecessary biopsy. Conclusions: The cavitation threshold may be used non-invasively to distinguish between high viscosity and low viscosity fluids in cysts and reduce biopsies on serous cysts.展开更多
The classical view of signaling between cells of immune system includes two major routes of intercellular communication:Through the release of extracellular molecules or a direct interaction between membrane bound rec...The classical view of signaling between cells of immune system includes two major routes of intercellular communication:Through the release of extracellular molecules or a direct interaction between membrane bound receptor and its membrane bound ligand,which initiate a cascade of signaling in target cell.However,recent studies indicate that besides these canonical modes of signaling there are also noncanonical routs of intercellular communications through membrane stripping/membrane exchange/trogocytosis,extracellular traps,exosomes and ectososmes/microparticles.In this review we discuss what are the components of noncanonical pathways of signaling and what role they play in immune cells interactions.展开更多
Prostate cancer is one of the most prevalent cancers in men,and there is no cure when it advances to a late stage.Antiandrogens are routinely used in clinics for prostate cancer treatment,and darolutamide(Daro)is the ...Prostate cancer is one of the most prevalent cancers in men,and there is no cure when it advances to a late stage.Antiandrogens are routinely used in clinics for prostate cancer treatment,and darolutamide(Daro)is the latest FDA-approved antiandrogen drug.^(1)Despite its efficacy,potential drug resistance poses significant challenges in the clinical setting.This study seeks to uncover the molecular mechanisms behind darolutamide resistance and identify potential therapeutic targets to overcome this resistance.展开更多
Since their first use in 1988,gadolinium-based magnetic resonance imaging(MRI)contrast agents(GBCAs)have been commonly and frequently applied for clinical MRI tests.The belief was that gadolinium is flushed out from t...Since their first use in 1988,gadolinium-based magnetic resonance imaging(MRI)contrast agents(GBCAs)have been commonly and frequently applied for clinical MRI tests.The belief was that gadolinium is flushed out from the body within several hours post-administration and is entirely safe for the patient.However,studies of the last decade showed that gadolinium accumulates in cells and tissues for many years.Such findings triggered the U.S.Food and Drug Administration(FDA)drug safety warnings and new recommendations to minimize repeated GBCA imaging when possible.In this mini-review,we describe ours and other studies on the effect of gadolinium retention on calcium signaling,actin cytoskeleton dynamics,and actin-related cell functions and structures.Because little information exists on the effects of GBCAs on immune cells,we describe here our novel findings showing that gadolinium ions,similar in size to calcium ions,may affect processes regulated by calcium,such as actin-related pathways.We showed that GBCA Dotarem causes macrophage elongation,disrupts organelle positioning,and changes the expression of inflammatory factors.These results indicate that GBCAs may affect patients'immune responses,which would be especially harmful to immunocompromised patients.展开更多
Radium-223(^(223)Ra)is a bone-seeking,alpha-particle-emitting radionuclide that is approved for the treatment of patients with metastatic prostate cancer and is currently being tested in clinical trials for primary an...Radium-223(^(223)Ra)is a bone-seeking,alpha-particle-emitting radionuclide that is approved for the treatment of patients with metastatic prostate cancer and is currently being tested in clinical trials for primary and metastatic cancers to the bone.^(223)Ra accumulates in mineralized bone areas with high bone turnover,where its effects are confined within 100μm of the bone-marrow interface due to the short tissue penetrance of the alpha particles.A recent clinical study has shown a significantly increased fracture rate associated with the administration of^(223)Ra,mostly in tumor-free bones.Importantly,the biological mechanisms underlying this bone fragility remain unclear.In this work,we combined micro-computed tomography and mechanical studies with ex vivo spatial biology analysis based on 3D fluorescence microscopy to clarify the effects of^(223)Ra on bone and key bone stromal cell components.We found that^(223)Ra caused major trabecular bone loss with no detectable impact on cortical bone.In addition,^(223)Ra impaired osteoblast bone-forming activity,which was paralleled by a transient increase in osteoclast number and long-term adipocyte formation.Overall,these results suggest that the impact of^(223)Ra on bone health is orchestrated by multiple bone stromal cell components.^(223)Ra-mediated trabecular bone loss was prevented by administration of zoledronic acid,which should always be combined with^(223)Ra.展开更多
Spatial statistics are crucial for analyzing clustering patterns in various spaces,such as the distribution of trees in a forest or stars in the sky.Advances in spatial biology,such as single-cell spatial transcriptom...Spatial statistics are crucial for analyzing clustering patterns in various spaces,such as the distribution of trees in a forest or stars in the sky.Advances in spatial biology,such as single-cell spatial transcriptomics,enable researchers to map gene expression patterns within tissues,offering unprecedented insights into cellular functions and disease pathology.Common methods for deriving spatial relationships include density-based methods(quadrat analysis,kernel density estimators)and distance-based methods(nearest-neighbor distance[NND],Ripley’s K function).While density-based methods are effective for visualization,they struggle with quantification due to sensitivity to parameters and complex significance tests.In contrast,distance-based methods offer robust frameworks for hypothesis testing,quantifying spatial clustering or dispersion,and facilitating comparisons with models such as uniform random distributions or Poisson processes[1,2].展开更多
Cytotoxic T lymphocytes （CTLs） and natural killer （NK） cells contribute to the body＇s immune defenses. Current chimeric antigen receptor （CAR）-modified T cell immunotherapy shows strong promise for treating var...Cytotoxic T lymphocytes （CTLs） and natural killer （NK） cells contribute to the body＇s immune defenses. Current chimeric antigen receptor （CAR）-modified T cell immunotherapy shows strong promise for treating var- ious cancers and infectious diseases. Although CAR- modified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use. To alleviate these disadvantages of CAR-modified T cell immunotherapy, additional cyto- toxic cell-mediated immunotherapies are urgently nee- ded. The unique biology of NK cells allows them to serve as a safe, effective, alternative immunotherapeutic strategy to CAR-modified T cells in the clinic. While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood, the for- mation of the immunological synapse （IS） between CAR- modified T or NK cells and their susceptible target cells is known to be essential. The role of the IS in CAR T and NK cell immunotherapies will allow scientists to harness the power of CAR-modified T and NK cells to treat can- cer and infectious diseases. In this review, we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus （HIV）, and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy, as well as the importance of understanding the molecular mechanisms of CAR-modified T cell- or NK cell-medi- ated cytotoxicity and side effects, with a focus on the CAR-modified NK cell IS.展开更多
Despite extensive studies on CD4^＋CD25^＋ regulatory T cells （Tregs） during the past decade, the progress on their clinical translation remains stagnant. Mounting evidence suggests that naturally occurring CD8^＋CD...Despite extensive studies on CD4^＋CD25^＋ regulatory T cells （Tregs） during the past decade, the progress on their clinical translation remains stagnant. Mounting evidence suggests that naturally occurring CD8^＋CD122^＋ T cells are also Tregs with the capacity to inhibit T-cell responses and suppress autoimmunity as well as alloimmunity. In fact, they are memory-like Tregs that resemble a central memory T cell （TcM） phenotype. The mechanisms underlying their suppression are still not well understood, although they may include IL-IO production. We have recently demonstrated that programmed death-1 （PD-1） expression distinguishes between regulatory and memory CD8^＋CD122^＋ T cells and that CD8^＋CD122^＋ Tregs undergo faster homeostatic proliferation and are more potent in the suppression of allograft rejection than conventional CD4^＋CD25^＋ Tregs. These findings may open a new line of investigation for accelerating effective Treg therapies in the clinic. In this review, we summarize the significant progress in this promising field of CD8^＋CD122^＋ Treg research and discuss their phenotypes, suppressive roles in autoimmunity and alloimmunity, functional requirements, mechanisms of action and potential applications in the clinic.展开更多
Nanocomposite fibers have attracted intensive attentions owing to their promising applications in various fields. However, the fabrication of nanocomposite fibers with super toughness and strong strength under mild co...Nanocomposite fibers have attracted intensive attentions owing to their promising applications in various fields. However, the fabrication of nanocomposite fibers with super toughness and strong strength under mild conditions remains a great challenge. Here we present a facile flow-induced assembly strategy for the development of super-tough and strong nanocomposite fibers with highly ordered carbon nanotubes (CNTs), which can be induced by directional and fast flow on a grooved hydrogel surface. The prepared nanocomposite fibers show excellent mechanical properties, with a tensile strength up to 643±27 MPa and toughness as high as 77.3±3.4 MJ m^-3 at ultimate strain of 14.8±1.5%. This versatile and efficient flow-induced alignment strategy represents a promising direction for the development of high-performance nanocomposites for practical applications.展开更多
The differentiation status of neuroblastoma （NB） strongly correlates with its clinical outcomes; however, the molecular mechanisms driving maintenance of sternness and differentiation remain poorly understood. Here,...The differentiation status of neuroblastoma （NB） strongly correlates with its clinical outcomes; however, the molecular mechanisms driving maintenance of sternness and differentiation remain poorly understood. Here, we show that plant homeodomain finger-containing protein 20 （PHF20） functions as a critical epigenetic regulator in sustaining stem cell-like phenotype of NB by using CRISPR/Casg-based targeted knockout （KO） for high-throughput screening of gene function in NB cell differentiation. The expression of PHF20 in NB was significantly associated with high aggressiveness of the tumor and poor outcomes for NB patients. Deletion of PHF20 inhibited NB cell proliferation, invasive migration, and stem ceU-Uke traits. Mechanistically, PHF20 interacts with poly（ADP-ribose） polymerase 1 （PARP1） and directly binds to promoter regions of octamer-binding transcription factor 4 （OCT4） and sex determining region Y-box 2 （SOX2） to modulate a histone mark associated with active transcription, trimethylation of lysine 4 on histone H3 protein subunit （H3K4me3）. Overexpression of OCT4 and SOX2 restored growth and progression of PHF20 KO tumor cells. Consistently, OCT4 and SOX2 protein levels in clinical NB specimens were positively correlated with PHF20 expression. Our results establish PHF20 as a key driver of NB stem cell-like properties and aggressive behaviors, with implications for prognosis and therapy.展开更多
基金supported by Warren Alpert Foundation and Houston Methodist Academic Institute Laboratory Operating Fund(to HLC).
文摘Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.
基金Supported by Houston Methodist DeBakey Heart and Vascular Center Grant.
文摘BACKGROUND Significant gaps in guideline-directed medical therapy(GDMT)for heart failure(HF)stem from shortages of cardiologists and advanced HF providers,as well as a lack of optimal HF management knowledge among hospitalists.This study compared the impact of optimal medical therapy in HF(OMT-HF)certification on GDMT implementation and patient outcomes between an intervention group(IG)of hospitalists and a standard-of-care comparison group(SOC-CG).METHODS This study was implemented from November 2022 to May 2023.Hospitalized car-diology patients with HF and left ventricular ejection fraction≤40%were rando-mized to IG or SOC-CG.Exclusion criteria included patients in cardiogenic shock,unable to consent,or at high risk.Follow-up was at 30 days post-discharge.Diffe-rences between groups were analyzed using Fisher’s exact test for categorical va-riables and Wilcoxon rank-sum or unpaired t-test for continuous variables.Chan-ges in Minnesota Living with Heart Failure Questionnaire(MLWHFQ)scores were evaluated using a paired t-test.RESULTS IG patients had lower readmission rates[9(42.85%)vs 11(17.46%),P=0.03]and a decreased trend in mortality 30-day post discharge.IG patients also showed greater mean improvements in total(-27.03±24.59 vs-5.85±23.52,P<0.001),physical(-13.8±12.3 vs-2.71±11.16,P<0.001)and emotional(-4.76±8.10 vs-1.42±5.98)dimensions on the MLWHFQ compared to SOC-CG,however,change in emotional dimension did not reach statistical significance.CONCLUSION Hospitalist OMT-HF certification may lead to better 30-day outcomes in hospitalized HF patients including quality of life,mortality and readmission rates.Larger prospective studies are warranted to validate these findings.
基金financial support from the following sources: National Natural Science Foundation of China (No. 81601632)the Natural Science Foundation of Jiangsu Province (No. SBK2016041233)+3 种基金the Fundamental Research Funds for Central Universities(No. 021314380067)Thousand Talents Program for Young Researchers, NIH (No. 1R21CA190024-01)DOD (No. W81XWH-12-1-0414)Houston Methodist Research Institute
文摘More recently, the biomedical applications of MnO2 in bioanalysis, cell imaging, and drug delivery as a result of their appealing physicochemical properties, have been reported and expanded rapidly. However, research on a near infrared （NIR） photothermal response of MnO2 was ignored. In this work, we reported a facile, one-pot method to synthesis of bovine serum albumin （BSA）-reduced and stabilized MnO2 nanoparticles （BSA-MnO2 NPs） with good aqueous dispersibility and high biocompatibility. And we also showed for the first time that BSA-MnO2 NPs displayed superior NIR photothermal efficiency and photostability which demonstrated as a novel class of photothermal antitumor agent.
基金The financial supports from NSF(CMMI-1405355)and ACS Petroleum Research Fund(53780-DNI7)are gratefully acknowledged.
文摘With appropriate stimuli,such as heat,humidity,or magnetic field,shape memory polymers(SMPs)can recover to their original shapes from temporary,programmed states.Using thermal responsive SMPs as substrates,we demonstrate a simple method to realize hybrid surface morphologies through confined thin film wrinkling in localized areas.The bilayer system was fabricated by depositing a layer of aluminum thin?lm on top of a SMP substrate programmed with a tensile strain.After the system was heated by a heating wire,hybrid wrinkling patterns were formed in a confined circular area around the heat source,with an inner spoke pattern and an outer ring pattern.Wrinkling patterns showed good symmetry,and the size of the wrinkling area can be tuned by controlling the heat input.This study o?ers a simple but effective approach to fabricate hybrid morphological features in micro-scale.With appropriate stimuli,such as heat,humidity,or magnetic field,shape memory polymers(SMPs)can recover to their original shapes from temporary,programmed states.Using thermal responsive SMPs as substrates,we demonstrate a simple method to realize hybrid surface morphologies through confined thin film wrinkling in localized areas.The bilayer system was fabricated by depositing a layer of aluminum thin?lm on top of a SMP substrate programmed with a tensile strain.After the system was heated by a heating wire,hybrid wrinkling patterns were formed in a confined circular area around the heat source,with an inner spoke pattern and an outer ring pattern.Wrinkling patterns showed good symmetry,and the size of the wrinkling area can be tuned by controlling the heat input.This study offers a simple but effective approach to fabricate hybrid morphological features in micro-scale.
基金the Coulter Foundation and NIH (NIH/NCI 1R21CA156078) for their funding of this project
文摘Convection-enhanced delivery （CED） is a promising technique leveraging pressure-driven flow to increase penetration of infused drugs into interstitial spaces. We have developed a fiberoptic microneedle device for inducing local sub-lethal hyperthermia to further improve CED drug distribution volumes, and this study seeks to quantitatively characterize this approach in agarose tissue phantoms. Infusions of dye were conducted in 0.6% （w/w） agarose tissue phantoms with isothermal conditions at 15 ℃, 20℃, 25 ℃, and 30 ℃. Infusion metrics were quantified using a custom shadowgraphy setup and image- processing algorithm. These data were used to build an empirical predictive temporal model of distribution volume as a function of phantom temperature. A second set of proof- of-concept experiments was conducted to evaluate a novel fiberoptic device capable of generating local photothermal heating during fluid infusion. The isothermal infusions showed a positive correlation between temperature and distribution volume, with the volume at 30℃ showing a 7-fold increase at 100 min over the 15 ℃ isothermal case. Infusions during photothermal heating （1064 nm at 500 mW） showed a similar effect with a 3.5-fold increase at 4 h over the control （0 mW）. These results and analyses serve to provide insight into and characterization of heat-mediated enhancement of volumetric dispersal.
文摘B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial–mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.
基金supported by the Atlantis International (Grant P11GJ10-0067)
文摘The high demand for lung transplants cannot be matched by an adequate number of lungs from donors. Since fully ex-novo lungs are far from being feasible, tissue engineering is actively considering implantation of engineered lungs where the devitalized structure of a donor is used as scaffold to be repopulated by stem cells of the receiving patient. A decellularized donated lung is treated inside a bioreactor where transport through the tracheobronchial tree (TBT) will allow for both deposition of stem cells and nourishment for their subsequent growth, thus developing new lung tissue. The key concern is to set optimally the boundary conditions to utilize in the bioreactor. We propose a predictive model of slow liquid ventilation, which combines a one-dimensional (1-D) mathematical model of the TBT and a solute deposition model strongly dependent on fluid velocity across the tree. With it, we were able to track and drive the concentration of a generic solute across the airways, looking for its optimal distribution. This was given by properly adjusting the pumps’ regime serving the bioreactor. A feedback system, created by coupling the two models, allowed us to derive the optimal pattern. The TBT model can be easily invertible, thus yielding a straightforward flow/pressure law at the inlet to optimize the efficiency of the bioreactor.
文摘BACKGROUND The impact of pancreatic tumor location on patient survival has been studied in large national data-based analyses which yielded controversial results.AIM To explore if pancreatic head cancer(PHC)and pancreatic body/tail cancer(PBTC)have different overall survival(OS),molecular signature and response to chemotherapy.METHODS We retrospectively queried patient records from July 2016 to June 2020 in our institution.Patient demographics,cancer stage on diagnosis,tumor location,somatic mutations,treatment,and survival are recorded and analyzed.A test is considered statistically significant if the P value was<0.05.RESULTS We reviewed 101 patients with complete records,among which 67(66.34%)were PHC and 34(33.66%)were PBTC.More PHC were diagnosed at younger age[61.49 vs 68.97,P=0.010],earlier stages(P=0.006)and underwent surgical resection(P=0.025).There were no significant differences among all mutations and pathways studied except for TP53 mutations(37.0%in PHC vs 70.0%in PBTC,P=0.03).OS was not statistically different between PHC and PBTC(P=0.636)in the overall population and in subgroups according to surgical resection status or stages.In terms of response to chemotherapy,chemotherapy regimens(FOLFIRINOX-based vs gemcitabine-based)didn’t impact disease free interval in those who had surgical resection in either PHC(P=0.546)or PBTC(P=0.654),or the duration of response to first line palliative treatment in those with advanced disease in PHC(P=0.915)or PBTC(P=0.524).CONCLUSION Even though PHC and PBTC have similar poor OS and response to chemotherapy,the different presentations and molecular profiles indicate they are different diseases.Utilization of molecular profiling to develop targeted therapy for individualization of treatment is needed.
文摘BACKGROUND Colorectal cancer(CRC)is the third leading cause of cancer-related death in males and females in the United States.Approximately,20%-22%of patients have metastatic disease at the time of presentation,and 50%-60%will develop metastasis over the course of their disease.Despite advances in systemic therapies,there remains a paucity of effective third-and later-line therapies for patients with ongoing disease progression.However,rechallenging chemoresistant CRC tumors with previously administered therapies is an emerging concept that may be a life-prolonging option for heavily treated metastatic colorectal cancer(mCRC).CASE SUMMARY A 41-year-old man with no previous medical history initially presented with worsening diffuse abdominal tenderness.Computed tomography was significant for a splenic flexure mass and hepatic lesions concerning for metastatic disease.He underwent a colectomy with anastomosis.Postoperative pathology was diagnostic for moderately to well-differentiated adenocarcinoma(T4bN1bM1a).He received adjuvant 5-fluorouracil,leucovorin,and oxaliplatin(FOLFOX),but therapy was discontinued due to the development of atrial fibrillation.Additional workup indicated a carcinoembryonic antigen level of 508.2 ng/mL,and mutational analysis found that the tumor was microsatellite instability-high and KRAS/BRAF wild-type.He was started on irinotecan with oxaliplatin(IROX),and bevacizumab(14 cycles),developed disease progression,was transitioned to FOLFOX and cetuximab,and then eventually three cycles of pembrolizumab.Following disease progression,he was rechallenged with IROX therapy,as he previously responded well to oxaliplatin-based therapy.The IROX rechallenge provided this patient with a ten-month survival benefit,decreased metastatic burden,and marked improvement in his clinical condition.CONCLUSION Rechallenge of previous lines of well-tolerated systemic chemotherapy regimens may be a valuable therapeutic strategy in patients with heavily-treated mCRC.
基金supported by a National Ataxia Foundation Young Investigator-SCA Award,No.93000(to NZ).
文摘Decades of biochemical studies have advanced DNA beyond its primary role as genetic blueprint.DNAzymes are single-stranded enzymatic DNA molecules that do not exist in nature.They are ideal candidates for gene silencing owing to their scalability by solid-phase synthesis(without batch variations),reprogrammability by directed evolution and local sequence alterations,compatibility with diverse delivery methods,and capability of achieving high catalytic turnover independent of any auxiliary proteins.With these unique features,various artificially evolved DNAzymes have been employed as theranostic tools in designing biosensors and logic gates,RNA/DNA cleavage and ligation,phosphorylation and dephosphorylation,DNA photorepair,and peptide side-chain modifications,to name but a few(Ponce-Salvatierra et al.,2021).This perspective will focus on the functional aspects and therapeutic potentials of RNA-cleaving DNAzymes.
文摘Objectives: To demonstrate in vitro that changes in ultrasound cavitation threshold might be used for non-invasively distinguishing high viscosity mucinous fluid from low viscosity serous fluid in cystic masses, based on the facts that cavitation threshold increases with increasing viscosity and that cavitation microbubbles are observable with diagnostic ultrasound. Methods: An in vitro model of a cyst was designed using dilutions of ultrasonic gel, and the cavitation threshold of this model was determined using focused and unfocused ultrasound for bubble initiation and clinical ultrasound b-scan for detection. Results: Viscosities of dilutions between 0% and 30% gel were had viscosities measuring between 1.05 ± 0.08 cP and 6600 ± 875 cP. Inertial cavitation in the latter was determined to require an order of magnitude greater intensity, at 1 MHz and 100% duty cycle, than the former (>2.2 W/cm2 vs. <0.19 W/cm2) using unfocused ultrasound. A four-fold increase in the peak negative pressure was required to initiate significant bubble activity using 1.1 MHz and 50% duty cycle focused ultrasound in the 6600 cP fluid compared with the 1 cP fluid. Based on these results, it was estimated that a threshold could be defined that would result in no bubbles in 99.9% of mucinous cysts and just 22% of serous cysts. The remaining 78% of patients presenting with serous cysts would be positively identified by detection of bubbles, and would be spared an unnecessary biopsy. Conclusions: The cavitation threshold may be used non-invasively to distinguish between high viscosity and low viscosity fluids in cysts and reduce biopsies on serous cysts.
基金Supported by William Stamps Farish FundDonald D.Hammill Foundation
文摘The classical view of signaling between cells of immune system includes two major routes of intercellular communication:Through the release of extracellular molecules or a direct interaction between membrane bound receptor and its membrane bound ligand,which initiate a cascade of signaling in target cell.However,recent studies indicate that besides these canonical modes of signaling there are also noncanonical routs of intercellular communications through membrane stripping/membrane exchange/trogocytosis,extracellular traps,exosomes and ectososmes/microparticles.In this review we discuss what are the components of noncanonical pathways of signaling and what role they play in immune cells interactions.
基金supported by the US National Institutes of Health(No.R33AI133697 to Q.F.,R01CA211861 to B.H.).
文摘Prostate cancer is one of the most prevalent cancers in men,and there is no cure when it advances to a late stage.Antiandrogens are routinely used in clinics for prostate cancer treatment,and darolutamide(Daro)is the latest FDA-approved antiandrogen drug.^(1)Despite its efficacy,potential drug resistance poses significant challenges in the clinical setting.This study seeks to uncover the molecular mechanisms behind darolutamide resistance and identify potential therapeutic targets to overcome this resistance.
文摘Since their first use in 1988,gadolinium-based magnetic resonance imaging(MRI)contrast agents(GBCAs)have been commonly and frequently applied for clinical MRI tests.The belief was that gadolinium is flushed out from the body within several hours post-administration and is entirely safe for the patient.However,studies of the last decade showed that gadolinium accumulates in cells and tissues for many years.Such findings triggered the U.S.Food and Drug Administration(FDA)drug safety warnings and new recommendations to minimize repeated GBCA imaging when possible.In this mini-review,we describe ours and other studies on the effect of gadolinium retention on calcium signaling,actin cytoskeleton dynamics,and actin-related cell functions and structures.Because little information exists on the effects of GBCAs on immune cells,we describe here our novel findings showing that gadolinium ions,similar in size to calcium ions,may affect processes regulated by calcium,such as actin-related pathways.We showed that GBCA Dotarem causes macrophage elongation,disrupts organelle positioning,and changes the expression of inflammatory factors.These results indicate that GBCAs may affect patients'immune responses,which would be especially harmful to immunocompromised patients.
基金supported by Bayer HealthCare Pharmaceuticals Inc.(57440)Department of Defense,CDMRP-KCRP(KC210132P1,USA)+2 种基金University of Texas MD Anderson Cancer CenterCancer Prevention and Research Institute of Texas(RP230160,USA)National Institutes of Health(P41EB023833,P30CA016672,USA).
文摘Radium-223(^(223)Ra)is a bone-seeking,alpha-particle-emitting radionuclide that is approved for the treatment of patients with metastatic prostate cancer and is currently being tested in clinical trials for primary and metastatic cancers to the bone.^(223)Ra accumulates in mineralized bone areas with high bone turnover,where its effects are confined within 100μm of the bone-marrow interface due to the short tissue penetrance of the alpha particles.A recent clinical study has shown a significantly increased fracture rate associated with the administration of^(223)Ra,mostly in tumor-free bones.Importantly,the biological mechanisms underlying this bone fragility remain unclear.In this work,we combined micro-computed tomography and mechanical studies with ex vivo spatial biology analysis based on 3D fluorescence microscopy to clarify the effects of^(223)Ra on bone and key bone stromal cell components.We found that^(223)Ra caused major trabecular bone loss with no detectable impact on cortical bone.In addition,^(223)Ra impaired osteoblast bone-forming activity,which was paralleled by a transient increase in osteoclast number and long-term adipocyte formation.Overall,these results suggest that the impact of^(223)Ra on bone health is orchestrated by multiple bone stromal cell components.^(223)Ra-mediated trabecular bone loss was prevented by administration of zoledronic acid,which should always be combined with^(223)Ra.
基金Daniel Shafiee Kermany,Ju Young Ahn,Matthew Vasquez,Lin Wang,Kai Liu,Raksha Raghunathan,Jianting Sheng,Hong Zhao,and Stephen Tin Chi Wong are supported by NCI U01CA252553,NCI R01CA238727,NCI R01CA177909,NCI R01CA244413John S.Dunn Research Foundation,and Ting Tsung and Wei Fong Chao Foundation+3 种基金Xiang Hong-Fei Zhang,Zhan Xu,Xiaoxin Hao,Weijie Zhang are supported by US Department of Defense DAMD W81XWH-16-1-0073(Era of Hope Scholarship)NCI R01CA183878,NCI R01CA251950,NCI U01CA252553,DAMD W81XWH-20-1-0375Breast Cancer Research Foundation,and McNair Medical Institute.Vahid Afshar-Kharghan,Min Soon Cho,Wendolyn Carlos-AlcaldeHani Lee are supported by NCI R01CA177909,NCI R01CA016672,NCI R01CA275762,and NCI P50CA217685.
文摘Spatial statistics are crucial for analyzing clustering patterns in various spaces,such as the distribution of trees in a forest or stars in the sky.Advances in spatial biology,such as single-cell spatial transcriptomics,enable researchers to map gene expression patterns within tissues,offering unprecedented insights into cellular functions and disease pathology.Common methods for deriving spatial relationships include density-based methods(quadrat analysis,kernel density estimators)and distance-based methods(nearest-neighbor distance[NND],Ripley’s K function).While density-based methods are effective for visualization,they struggle with quantification due to sensitivity to parameters and complex significance tests.In contrast,distance-based methods offer robust frameworks for hypothesis testing,quantifying spatial clustering or dispersion,and facilitating comparisons with models such as uniform random distributions or Poisson processes[1,2].
文摘Cytotoxic T lymphocytes （CTLs） and natural killer （NK） cells contribute to the body＇s immune defenses. Current chimeric antigen receptor （CAR）-modified T cell immunotherapy shows strong promise for treating var- ious cancers and infectious diseases. Although CAR- modified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use. To alleviate these disadvantages of CAR-modified T cell immunotherapy, additional cyto- toxic cell-mediated immunotherapies are urgently nee- ded. The unique biology of NK cells allows them to serve as a safe, effective, alternative immunotherapeutic strategy to CAR-modified T cells in the clinic. While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood, the for- mation of the immunological synapse （IS） between CAR- modified T or NK cells and their susceptible target cells is known to be essential. The role of the IS in CAR T and NK cell immunotherapies will allow scientists to harness the power of CAR-modified T and NK cells to treat can- cer and infectious diseases. In this review, we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus （HIV）, and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy, as well as the importance of understanding the molecular mechanisms of CAR-modified T cell- or NK cell-medi- ated cytotoxicity and side effects, with a focus on the CAR-modified NK cell IS.
文摘Despite extensive studies on CD4^＋CD25^＋ regulatory T cells （Tregs） during the past decade, the progress on their clinical translation remains stagnant. Mounting evidence suggests that naturally occurring CD8^＋CD122^＋ T cells are also Tregs with the capacity to inhibit T-cell responses and suppress autoimmunity as well as alloimmunity. In fact, they are memory-like Tregs that resemble a central memory T cell （TcM） phenotype. The mechanisms underlying their suppression are still not well understood, although they may include IL-IO production. We have recently demonstrated that programmed death-1 （PD-1） expression distinguishes between regulatory and memory CD8^＋CD122^＋ T cells and that CD8^＋CD122^＋ Tregs undergo faster homeostatic proliferation and are more potent in the suppression of allograft rejection than conventional CD4^＋CD25^＋ Tregs. These findings may open a new line of investigation for accelerating effective Treg therapies in the clinic. In this review, we summarize the significant progress in this promising field of CD8^＋CD122^＋ Treg research and discuss their phenotypes, suppressive roles in autoimmunity and alloimmunity, functional requirements, mechanisms of action and potential applications in the clinic.
基金supported by the National Key R&D Program of China(2017YFA0207800)the National Natural Science Foundation of China(21574004)+4 种基金the National Natural Science Funds for Distinguished Young Scholar(21725401)the 111 project(B14009)the Fundamental Research Funds for the Central Universitiesthe National “Young Thousand Talents Program”the China Postdoctoral Science Foundation(2017M620012)
文摘Nanocomposite fibers have attracted intensive attentions owing to their promising applications in various fields. However, the fabrication of nanocomposite fibers with super toughness and strong strength under mild conditions remains a great challenge. Here we present a facile flow-induced assembly strategy for the development of super-tough and strong nanocomposite fibers with highly ordered carbon nanotubes (CNTs), which can be induced by directional and fast flow on a grooved hydrogel surface. The prepared nanocomposite fibers show excellent mechanical properties, with a tensile strength up to 643±27 MPa and toughness as high as 77.3±3.4 MJ m^-3 at ultimate strain of 14.8±1.5%. This versatile and efficient flow-induced alignment strategy represents a promising direction for the development of high-performance nanocomposites for practical applications.
基金This work was supported by grants from the National Natural Science Foundation of China （81572766 and 31771630）, the National Key Research and Development Program of China （2017YFA0103800）, Guangdong Innovative and Entrepreneurial Research Team Program （2016ZT06S029）, Guangdong Natural Science Foundation （2016A030313215 and 2016A030313238）, SYSU Young Teachers Training Program （16YKZD14） and grants （CA101795 and IU54CA210181） from U.S. National Cancer Institute, National Institutes of Health （NIH）, DOD （W81XWH-16- 1-0417）, and CPRIT （DP150099, RP170537, and RP150611）.
文摘The differentiation status of neuroblastoma （NB） strongly correlates with its clinical outcomes; however, the molecular mechanisms driving maintenance of sternness and differentiation remain poorly understood. Here, we show that plant homeodomain finger-containing protein 20 （PHF20） functions as a critical epigenetic regulator in sustaining stem cell-like phenotype of NB by using CRISPR/Casg-based targeted knockout （KO） for high-throughput screening of gene function in NB cell differentiation. The expression of PHF20 in NB was significantly associated with high aggressiveness of the tumor and poor outcomes for NB patients. Deletion of PHF20 inhibited NB cell proliferation, invasive migration, and stem ceU-Uke traits. Mechanistically, PHF20 interacts with poly（ADP-ribose） polymerase 1 （PARP1） and directly binds to promoter regions of octamer-binding transcription factor 4 （OCT4） and sex determining region Y-box 2 （SOX2） to modulate a histone mark associated with active transcription, trimethylation of lysine 4 on histone H3 protein subunit （H3K4me3）. Overexpression of OCT4 and SOX2 restored growth and progression of PHF20 KO tumor cells. Consistently, OCT4 and SOX2 protein levels in clinical NB specimens were positively correlated with PHF20 expression. Our results establish PHF20 as a key driver of NB stem cell-like properties and aggressive behaviors, with implications for prognosis and therapy.
