Characterizing Thermal Augmentation of Convection-Enhanced Drug Delivery with the Fiberoptic Microneedle Device

Convection-enhanced delivery(CED) is a promis ing 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 °C, 20 °C, 25 °C, and 30 °C. Infusion metrics were quantifled using a custom shadowgraphy setup and imageprocessing 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 °C showing a 7-fold increase at 100 min over the 15 °C isothermal case. Infusions during photothermal heating(1064 nm at 500 mW) showed a similar eff ect 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.

Optimal flow conditions of a tracheobronchial model to reengineer lung structures

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.

DNAzyme as a rising gene-silencing agent in theranostic settings

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.

Pancreatic head vs pancreatic body/tail cancer:Are they different?

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.

Chemotherapy rechallenge in metastatic colon cancer:A case report and literature review

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.

Potential Use of Ultrasonic Cavitation Threshold to Non-Invasively Differentiate Cystic Masses

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.

Noncanonical intercellular communication in immune response

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.

Exploiting fly models to investigate rare human neurological disorders

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.

A naturally occurring CD8^＋CD122^＋ T-cell subset as a memory-like Treg family

尽管有 CD4 + CD25 + 规章的 T 房间(Tregs ) 在过去的十年期间，在他们的临床的翻译以后的进步仍然保持停滞。增长证据建议那自然地发生的 CD8 + CD122 + T 房间也是有能力的 Tregs 禁止 T 房间回答并且象 alloimmunity 一样压制 autoimmunity。事实上，他们是像记忆的 Tregs 类似于一个中央记忆 T 房间(T 厘米 ) 显型。位于他们的抑制下面的机制仍然不好被理解，尽管他们可以包括 IL-10 生产。我们最近证明了那个规划 death-1 (PD-1 ) 表达式区分在之间规章并且存储器 CD8 + CD122 + T 房间和那 CD8 + CD122 + Tregs 经历更快的 homeostatic 增长并且比常规 CD4 + CD25 + Tregs。这些调查结果可以为在诊所加速有效 Treg 治疗打开调查的一根新线。在这评论，我们在 CD8 + CD122 + Treg 在诊所研究并且讨论他们的显型，在 autoimmunity 和 alloimmunity 的镇压角色，功能的要求，行动的机制和潜在的应用。

Highly biocompatible BSA-MnO_2 nanoparticles as an efficient near-infrared photothermal agent for cancer therapy

More recently, the biomedical applications of MnO_2 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 MnO_2 was ignored. In this work, we reported a facile, one-pot method to synthesis of bovine serum albumin(BSA)-reduced and stabilized MnO_2 nanoparticles(BSA-MnO_2 NPs) with good aqueous dispersibility and high biocompatibility. And we also showed for the first time that BSA-MnO_2 NPs displayed superior NIR photothermal efficiency and photostability which demonstrated as a novel class of photothermal antitumor agent.

水凝胶表面沟槽内液流诱导制备具有取向碳纳米管的超韧高强纳米复合纤维（英文）

纳米复合纤维由于其广泛的应用前景受到科学家的关注.但是在温和条件下制备具有优异断裂韧性与高强度的纳米复合纤维仍然面临很大的挑战.本文中,我们展示了一种简单的基于液流组装的策略用于制备具有超高断裂韧性与强度的纳米复合纤维.在准液态的水凝胶表面和重力的双重作用下,含有碳纳米管的水溶液可以沿水凝胶沟槽极快速地流动,从而诱导碳纳米管取向排列.我们制备出的纳米复合纤维拉伸强度和断裂韧性分别高达643±27 MPa和77.3±3.4 MJ m-3,极限断裂伸长率14.8±1.5%.这种具有较强普适性和高效率的液流诱导取向策略为高性能纳米复合纤维的实际应用提供了新的可行的发展方向.

Role of CD8^(+) regulatory T cells in organ transplantation

CD8^(+)T cells are regulatory T cells(Tregs)that suppress both alloimmunity and autoimmunity in many animal models.This class of regulatory cells includes the CD8^(+)CD28^(-),CD8^(+)CD103^(+),CD8^(+)FoxP3^(+)and CD8^(+)CD122^(+)subsets.The mechanisms of action of these regulatory cells are not fully understood;however,the secretion of immunosuppressive cytokines,such as interleukin(IL)-4,IL-10 and transforming growth factor beta(TGF-β)as well as the direct killing of target cells via Fas L/Fas and the perforin/granzyme B pathways have been demonstrated in various models.Further studies are necessary to fully understand the mechanisms underlying the suppressive effects of Tregs and to provide experimental support for potential clinical trials.We recently observed that CD8^(+)CD122^(+)Tregs more potently suppressed allograft rejection compared to their CD4^(+)CD25^(+)counterparts,supporting the hypothesis that CD8^(+)Tregs may represent a new and promising Treg family that can be targeted to prevent allograft rejection in the clinic.In this review,we summarize the progress in the field during the past 7-10 years and discuss CD8^(+)Treg phenotypes,mechanisms of action,and their potential clinical applications;particularly in composite tissue transplants in burn and trauma patients.

Cytokine regulation of immune tolerance

The immune system provides defenses against invading pathogens while maintaining immune tolerance to self-antigens.This immune homeostasis is harmonized by the direct interactions between immune cells and the cytokine environment in which immune cells develop and function.Herein,we discuss three non-redundant paradigms by which cytokines maintain or break immune tolerance.We firstly describe how anti-inflammatory cytokines exert direct inhibitory effects on immune cells to enforce immune tolerance,followed by discussing other cytokines that maintain immune tolerance through inducing CD_(4)^(+) Foxp_(3)^(+) regulatory T cells(Tregs),which negatively control immune cells.Interleukin(IL)-2 is the most potent cytokine in promoting the development and survival of Tregs,thereby mediating immune tolerance.IL-35 is mainly produced by Tregs,but its biology function remains to be defi ned.Finally,we discuss the actions of proinflammatory cytokines that breach immune tolerance and induce autoimmunity,which include IL-7,IL-12,IL-21,and IL-23.Recent genetic studies have revealed the role of these cytokines(or their cognate receptors)in susceptibility to autoimmune diseases.Taken together,we highlight in this review the cytokine regulation of immune tolerance,which will help in further understanding of human diseases that are caused by dysregulated immune system.

Chronic allograft rejection:A significant hurdle to transplant success

The state-of-the-art immunosuppression drugs do not ensure indefi nite transplant survival,and most transplants are continuously lost to chronic rejection even years posttransplantation.This form of rejection is responsible for long-term failure of transplanted organs.The mechanisms involved in development of chronic rejection are not well-understood.One of the main features of chronic rejection is progressive luminal narrowing of graft vessels,which results in compromised blood flow,ischemia,cell death,and finally graft failure.All the existing immunosuppressive regimens are targeting acute rejection,and at present there is no available therapy for prevention of chronic rejection.Chronic rejection involves two major,but interrelated responses:The first is the host immune response against the transplant mediated primarily by alloreactive T and B cells,and the second is injury and repair of the graft(vasculopathy of graft vessels).Here we focus on recent advances in understanding the cellular and molecular aspects of chronic transplant vasculopathy and function of macrophages,topics pivotal for development of novel antichronic rejection therapies.

Chemerin deficiency regulates adipogenesis is depot different through TIMP1

Adipocytes and immune cells are vital for the development of adipose tissue.Adi-pokines secreted by adipocytes regulate adipogenesis and body metabolism.Chemerin is one of the adipokines.However,the function and mechanism of chemerin in adipose tissue are not fully illuminated.Compared with wild type(WT)mice,Rarres2^(-/-)mice gained weight and significantly increased fat distribution in subcutaneous adipose tissue(SAT),rather than visceral adipose tissue(VAT)on high fat diet(HFD).PPARg and C/EBPa,the master regulators of adipogenesis,were up-regulated in SAT and down-regulated in VAT in Rarres2^(-/-)mice comparing with WT mice.Inspite of chemerin deficiency or not,the ratio of adipocyte-progenitors to total cells and the differentiation capacity of adipocyte-progenitors were similar in SAT and VAT,but macrophage infiltration in VAT was more severe than in SAT in Rarres2^(-/-)mice.Furthermore,CD45þimmune cells supernatant from Rarres2^(-/-)SAT pro-moted the differentiation of adipocyte-progenitors and 3T3-L1 cells.Adipokine array assay of CD45þimmune cells supernatant revealed that metalloproteinase inhibitor 1(TIMP1),an in-hibitor of adipogenesis,was reduced in Rarres2^(-/-)SAT,but increased in Rarres2^(-/-)VAT.As we specifically knocked down chemerin in SAT,TIMP1 was down-regulated and adipogenesis was promoted with reducing infiltration of macrophages.The present study demonstrates that the effects of chemerin on adipose tissue is depot different,and specific knock down chemerin in SAT promote adipogenesis and improve glucose tolerance test(GTT)and insulin tolerance test(ITT).This suggests a potential therapeutic target for chemerin in the treatment of obesity related metabolic disorder.

血液中羟基化缓激肽作为肿瘤厌氧指标的研究

组织缺氧在消化系统、呼吸系统、肾脏疾病和癌症等多种疾病的发生发展中起到关键作用.然而,由于缺乏快速、准确和非侵入性的检测方法,评估组织缺氧情况和预测患者的预后结果仍然具有非常大的挑战性.本文假设血液中Hyp-BK/BK比率可以作为缺氧检测的标志物,以胰腺癌作为研究模型,通过监测Hyp-BK/BK比率可以预测组织缺氧水平以及抗肿瘤治疗的预后情况.研究表明,缺氧条件下肿瘤组织中高表达的P4HA1和治疗前患者血液样本中Hyp-BK/BK比率升高有关,并且两者都与患者预后不良相关.这些结果有力地表明血液中Hyp-BK/BK比率可以作为非侵入性的组织缺氧标志物,对胰腺癌的预后和治疗效果进行预测.

Nanotrap-enabled quantification of KRAS-induced peptide hydroxylation in blood for cancer early detection

Circulating peptide is a potential source of biomarkers for cancer detection.However,the existence of large molecular weight proteins in plasma have a disastrous effect on circulating peptides isolating and detecting.Herein,nanotrap fractionation following by mass spectrometry have been applied to quantify the levels of bradykinin (BK) and hydroxylated bradykinin (Hyp-BK) as a relative measure of KRAS-regulated prolyl-4-hydroxylase alpha-1 (P4HA1) which may serve as early diagnosis marker for pancreatic ductal adenocarcinoma (PDAC).We found that P4HA1 can be upregulated by KRASG12v,which is a PDAC driver mutation,using HPNE/KRAS and HPNE cells.And we revealed that P4HA1 is overexpressed in PDAC tumors,compared to normal and inflamed pancreatic tissues.RNA interference revealed that P4HA1 activity was primarily responsible for Hyp-BK production.Mass spectrometry analysis revealed that plasma Hyp-BK/BK ratio was higher in PDAC than pancreatitis patients and healthy controls,while the area under the receiver operating characteristic (ROC) curve (AUC) is 0.8209 (95%Cl,0.7269-0.9149).The Hyp-BK/BK association with PDAC was reproduced in another cohort,where this ratio was found to increase with advancing tumor stage.These novel findings paved the way for wider applications of Nanotrap coupled mass spectrometry as a powerful tool for revealing biosignatures from plasma.

Chemical-sensitive graphene modulator with a memory effect for internet-of-things applications

Modern internet of things(IoTs)and ubiquitous sensor networks could potentially take advantage of chemically sensitive nanomaterials and nanostructures.However,their heterogeneous integration with other electronic modules on a networked sensor node,such as silicon-based modulators and memories,is inherently challenging because of compatibility and integration issues.Here we report a novel paradigm for sensing modulators:a graphene field-effect transistor device that directly modulates a radio frequency(RF)electrical carrier signal when exposed to chemical agents,with a memory effect in its electrochemical history.We demonstrated the concept and implementation of this graphene-based sensing modulator through a frequency-modulation(FM)experiment conducted in a modulation cycle consisting of alternating phases of air exposure and ethanol or water treatment.In addition,we observed an analog memory effect in terms of the charge neutrality point of the graphene,Vcnp,which strongly influences the FM results,and developed a calibration method using electrochemical gate-voltage pulse sequences.This graphenebased multifunctional device shows great potential for use in a simple,low-cost,and ultracompact nanomaterial-based nodal architecture to enable continuous,real-time event-based monitoring in pervasive healthcare IoTs,ubiquitous security systems,and other chemical/molecular/gas monitoring applications.