Efficacy of parasternal peripheral nerve catheters versus no block for median sternotomy: a single-centre retrospective study.

Background: Sternal pain after cardiac surgery results in considerable discomfort. Single-injection parasternal fascial plane blocks have been shown to reduce pain scores and opioid consumption during the first 24 h after surgery, but the efficacy of continuous infusion has not been evaluated. This retrospective cohort study examined the effect of a continuous infusion of local anaesthetic through parasternal catheters on the integrated Pain Intensity and Opioid Consumption (PIOC) score up to 72 h. Methods: We performed a retrospective analysis of patients undergoing cardiac surgery with median sternotomy at a single academic centre before and after the addition of parasternal nerve catheters to a standard multimodal analgesic protocol. Outcomes included PIOC score, total opioid consumption in oral morphine equivalents, and time-weighted area under the curve pain scores up to 72 h after surgery. Results: Continuous infusion of ropivacaine 0.1% through parasternal catheters resulted in a significant reduction in PIOC scores at 24 h (-62, 95% confidence interval -108 to -16; P<0.01) and 48 h (-50, 95% CI -97 to -2.2; P=0.04) compared with no block. A significant reduction in opioid consumption up to 72 h was the primary factor in reduction of PIOC. Conclusions: This study suggests that continuous infusion of local anaesthetic through parasternal catheters may be a useful addition to a multimodal analgesic protocol in patients undergoing cardiac surgery with sternotomy. Further prospective study is warranted to determine the full benefits of continuous infusion compared with single injection or no block.

Hydric physiology and ecology of a federally endangered desert lizard.

Animals can respond to extreme climates by behaviourally avoiding it or by physiologically coping with it. We understand behavioural and physiological thermoregulation, but water balance has largely been neglected. Climate change includes both global warming and changes in precipitation regimes, so improving our understanding of organismal water balance is increasingly urgent. We assessed the hydric physiology of US federally endangered blunt-nosed leopard lizards (Gambelia sila) by measuring cutaneous evaporative water loss (CEWL), plasma osmolality and body condition. Measurements were taken throughout their active season, the short period of year when these lizards can be found aboveground. Compared to a more mesic species, G. sila had low CEWL which is potentially desert-adaptive, and high plasma osmolality that could be indicative of dehydration. We hypothesized that throughout the G. sila active season, as their habitat got hotter and drier, G. sila would become more dehydrated and watertight. Instead, CEWL and plasma osmolality showed minimal change for females and non-linear change for males, which we hypothesize is connected to sex-specific reproductive behaviours and changes in food availability. We also measured thermoregulation and microhabitat use, expecting that more dehydrated lizards would have lower body temperature, poorer thermoregulatory accuracy and spend less time aboveground. However, we found no effect of CEWL, plasma osmolality or body condition on these thermal and behavioural metrics. Finally, G. sila spends considerable time belowground in burrows, and burrows may serve not only as essential thermal refugia but also hydric refugia.

Characterising the behaviours in most severe and least severe emotional outbursts in young people.

Emotional outbursts are displays of intense, challenging behaviour and are prevalent in individuals with neurodevelopmental disorders. Outbursts present a danger to individuals and their carers and are cited as reasons for referral to mental health services. However, it is currently unclear how the characteristics of outbursts may determine their severity. Carers (n = 214) of individuals aged between 6 and 25 and experiencing outbursts at least once per month completed the Emotional Outburst Questionnaire. Questionnaire items were used to compare behaviours observed in most severe and least severe outbursts through quantitative and content analyses of open ended data. Signs of physiological arousal and aggression were seen significantly more in most severe outbursts compared to least severe outbursts. Least severe outbursts were seen more frequently, but most severe outbursts were reported to have a longer duration, be at a higher intensity, and have a longer recovery time. Additionally, associations were found between reduced eye contact and most severe outbursts, as well as expression of suicidal ideation and most severe outbursts. Certain behaviours, notably forms of aggression and physiological arousal, are associated with most severe outbursts. Findings of this study may allow future work examining cross-disorder differences in outbursts to inform targeted interventions aiming to reduce outburst severity and impact. Additionally, identification of such outburst characteristics could aid in measurement of outburst severity, which would allow for more reliable and valid studies on outburst interventions.

Preliminary psychometric properties of the Brazilian Portuguese version of the emotional outburst questionnaire.

This study focuses on the cross-cultural adaptation of the Emotional Outburst Questionnaire (EOQ) to Brazilian Portuguese and preliminarily assesses its predictive validity. The EOQ evaluates aspects of emotional outbursts (EO), including frequency, duration, intensity, types, associated behaviours, recovery time, triggers, and effectiveness of calming strategies. Two independent translators performed the translation, with subsequent synthesis and analysis revealing that only 33 items (24.81%) required revision. Among these, one item needed partial modification, and two needed total modification. The study demonstrated strong content validity and adaptation in terms of conceptual, idiomatic, and semantic aspects. The EOQ's predictive validity was assessed by analysing the interruption of mental health services in Brazil due to Covid-19 (T1) compared to when services resumed after social distancing measures were lifted (T2). Parents of 25 individuals with developmental disabilities (ASD, DS and ID), with a mean of 11 y/o, mostly male (76%), completed the EOQ. Service interruption during T1 led to increased frequency and duration of severe emotional outbursts reported by caregivers compared to T2 (frequency: p < .001; duration: p = 0.05). This suggests that the EOQ exhibits predictive validity and sensitivity to changes influenced by individual contexts. These findings highlight the EOQ's potential as an outcome measure for intervention development.

Comparative Analysis of Antibacterial and Wound Healing Activities of Chitosan and Povidone-Iodine-Based Hydrogels.

PURPOSE: This study aimed to compare the antibacterial and wound healing efficacies of chitosan hydrogel with povidone-iodine (PI) hydrogel. METHODS: The in vitro antibacterial activities of chitosan and PI hydrogels against Staphylococcus aureus and Escherichia coli were evaluated. Nine 6- to 8-week-old male Sprague-Dawley rats were divided into plain, PI, and chitosan hydrogel groups. Each rat received two 10-mm full-thickness dorsal wounds using an excisional splinting model. Each wound was treated with 0.2 mL of gel thrice over the course of 3 postoperative weeks. Weekly observations were conducted, and at the end of the third postoperative week, the rats were killed for histopathological and quantitative polymerase chain reaction evaluations. Data analysis included both 2- and 1-way analyses of variance. RESULTS: Chitosan hydrogel exhibited comparable in vitro antibacterial activity and a significantly enhanced in vivo wound closure rate compared with PI hydrogel. Three weeks after the surgery, the chitosan hydrogel group demonstrated marked differences in wound repair (P < 0.01). Histologically, increased collagen deposition was observed with chitosan hydrogel treatment. Immunohistochemistry for CD68 revealed a lower number of macrophages in the wounds treated with chitosan hydrogel. Quantitative polymerase chain reaction analysis indicated a superior collagen 1 to 3 ratio and reduced expression of proinflammatory cytokine mRNAs (interleukin 1b, interleukin 6, tumor necrosis factor α, and interferon γ) in the chitosan hydrogel group. CONCLUSION: Chitosan hydrogel demonstrates the potential to serve as an effective alternative to PI hydrogel, providing enhanced wound healing capabilities while maintaining comparable antimicrobial properties.

Osseointegration Foundation Charity Overdenture Program Study: Part 2.

This assessment evaluated the clinical feasibility of using narrow-diameter implants to support a mandibular overdenture. Twelve patients presenting with an edentulous mandible were recruited from nine dental offices. Each patient received two to four implants in the mandible. The implants were placed without additional bone augmentation, and a total of 36 implants were placed. All sites achieved satisfactory crestal bone stability and soft tissue maintenance 1 year after the final prosthetic restoration. This investigation was supported by the Osseointegration Foundation, working in conjunction with the Zest Anchors implant company. There are three basic valuable activities that emerge from a professional foundation, which were reflected in this case study. They include disseminating information to practitioners, persuading young clinicians to become research investigators, and reaching out to patients in need of treatment who cannot afford it without a charitable opportunity.

A Rare Case of Diffuse Alveolar Hemorrhage Caused by Fentanyl Inhalation.

Diffuse alveolar hemorrhage (DAH) is a rare but life-threatening pulmonary disorder characterized by blood accumulation in alveolar spaces, often associated with autoimmune diseases and infections. Drug-induced causes of DAH, including inhalation of substances like fentanyl, are emerging concerns. A 40-year-old male with bipolar disorder and polysubstance abuse presented with altered mental status and hemoptysis after inhaling an unknown substance. Physical examination revealed respiratory distress, pinpoint pupils, and severe hypoxemia. Naloxone administration improved his condition. The workup showed negative infection markers, positive fentanyl-specific urine test, and diffuse bilateral opacities on imaging. Bronchoalveolar lavage confirmed DAH with >20% hemosiderin-laden macrophages. Steroid treatment resulted in marked improvement. Drug-induced DAH, such as fentanyl inhalation, should be considered in patients with altered mental status and pulmonary symptoms following substance use. Comprehensive evaluation and targeted treatment are crucial for optimal outcomes.

Different Gabapentin and Pregabalin Dosages for Perioperative Pain Control in Patients Undergoing Spine Surgery: A Systematic Review and Network Meta-Analysis.

IMPORTANCE: Patients undergoing spine surgery often experience severe pain. The optimal dosage of pregabalin and gabapentin for pain control and safety in these patients has not been well established. OBJECTIVE: To evaluate the associations of pain, opioid consumption, and adverse events with different dosages of pregabalin and gabapentin in patients undergoing spine surgery. DATA SOURCES: PubMed/MEDLINE, Embase, Web of Science, Cochrane library, and Scopus databases were searched for articles until August 7, 2021. STUDY SELECTION: Randomized clinical trials conducted among patients who received pregabalin or gabapentin while undergoing spine surgery were included. DATA EXTRACTION AND SYNTHESIS: Two investigators independently performed data extraction following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) reporting guideline. The network meta-analysis was conducted from August 2022 to February 2023 using a random-effects model. MAIN OUTCOMES AND MEASURES: The primary outcome was pain intensity measured using the Visual Analog Scale (VAS), and secondary outcomes included opioid consumption and adverse events. RESULTS: Twenty-seven randomized clinical trials with 1861 patients (median age, 45.99 years [range, 20.00-70.00 years]; 759 women [40.8%]) were included in the systematic review and network meta-analysis. Compared with placebo, the VAS pain score was lowest with gabapentin 900 mg per day, followed by gabapentin 1200 mg per day, gabapentin 600 mg per day, gabapentin 300 mg per day, pregabalin 300 mg per day, pregabalin 150 mg per day, and pregabalin 75 mg per day. Additionally, gabapentin 900 mg per day was found to be associated with the lowest opioid consumption among all dosages of gabapentin and pregabalin, with a mean difference of -22.07% (95% CI, -33.22% to -10.92%) for the surface under the cumulative ranking curve compared with placebo. There was no statistically significant difference in adverse events (nausea, vomiting, and dizziness) among all treatments. No substantial inconsistency between direct and indirect evidence was detected for all outcomes. CONCLUSIONS AND RELEVANCE: These findings suggest that gabapentin 900 mg per day before spine surgery is associated with the lowest VAS pain score among all dosages. In addition, no differences in adverse events were noted among all treatments.

Enhancing adoptive T-cell therapy with fucoidan-based IL-2 delivery microcapsules.

Adoptive cell therapy (ACT) with antigen-specific T cells is a promising treatment approach for solid cancers. Interleukin-2 (IL-2) has been utilized in boosting the efficacy of ACT. However, the clinical applications of IL-2 in combination with ACT is greatly limited by short exposure and high toxicities. Herein, a complex coacervate was designed to intratumorally deliver IL-2 in a sustained manner and protect against proteolysis. The complex coacervate consisted of fucoidan, a specific IL-2 binding glycosaminoglycan, and poly-l-lysine, a cationic counterpart (FPC2). IL-2-laden FPC2 exhibited a preferential bioactivity in ex vivo expansion of CD8+T cells over Treg cells. Additionally, FPC2 was embedded in pH modulating injectable gel (FPC2-IG) to endure the acidic tumor microenvironment. A single intratumoral administration of FPC2-IG-IL-2 increased expansion of tumor-infiltrating cytotoxic lymphocytes and reduced frequencies of myeloid populations. Notably, the activation and persistency of tumor-reactive T cells were observed only in the tumor site, not in the spleen, confirming a localized effect of FPC2-IG-IL-2. The immune-favorable tumor microenvironment induced by FPC2-IG-IL-2 enabled adoptively transferred TCR-engineered T cells to effectively eradicate tumors. FPC2-IG delivery system is a promising strategy for T-cell-based immunotherapies.

The role of emotion regulation and choice repetition bias in the ultimatum game.

Social decision-making is commonly explored in the context of adult responder behavior in the ultimatum game. Responder behavior in the game has been proposed to be the consequence of two competing systems that control behavior: an affective system, which promotes an emotional response to unfair offers, and a deliberative system, which instead encourages a rational response to maximize in-game gains. In a secondary analysis of ultimatum game data in children and adolescents (N = 429), the present study demonstrated that trial-level metrics of responder behavior were reflective of a dual systems framework. However, no consistent relationship was found between responder behavior and trait-level measures of emotion regulation. Choice history was found to influence all measures of responder behavior in the game. These results support a dual systems account of social decision-making in children and adolescents and highlight choice repetition bias as an additional factor influencing decision-making within the ultimatum game. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Cross-Cultural Comparison of the Contexts Associated with Emotional Outbursts.

The causal relationship between emotional outbursts and emotion dysregulation is proposed to be heterogeneous, but cultural influences have not been considered despite established cultural differences in emotional processes (e.g., increased motivation to suppress emotions in interdependent cultures). Responses to the Brazilian Portuguese version of the Emotional Outburst Questionnaire were collected from 327 caregivers of young people (6-25 years) with autism spectrum disorder, Down's syndrome, or intellectual disability. Responses were compared to a previous sample of 268 responses from the English version of the questionnaire. The latent factor structure of the contextual items was measurement invariant across both versions. The Brazilian responses were classified into three distinct clusters (Sensory Sensitivity; Perceived Safety; Perceived Unsafety) which considerably overlapped with the English clusters.

Reactive Oxygen Species Suppressive Kraft Lignin-Gelatin Antioxidant Hydrogels for Chronic Wound Repair.

Chronic wound is difficult to repair because the normal wound healing mechanism is inhibited by the continuous inflammatory response. The delayed inflammatory responses generate high level of reactive oxygen species (ROS) at the wound sites, which leads to a longer inflammatory phase and induces a vicious cycle that interferes with the normal wound healing process. Therefore, ROS scavenging is an important factor for chronic wound healing. In this study, antioxidant hydrogel is developed by cross-linking kraft lignin, an antioxidant agent, and gelatin (Klig-Gel). Klig-Gel hydrogel is fabricated via ring opening reaction with epichlorohydrin as a cross-linker. High ROS scavenging activities are confirmed by various antioxidant evaluations, and in vitro natural antioxidant expression tests show reduction of oxidative stress. Mechanical properties of Klig-Gel hydrogel are tailorable by introducing different amount of kraft lignin to the hydrogel system. Biocompatibility is confirmed regardless of the kraft lignin content. Klig-Gel hydrogel is a promising ROS scavenging material that can be applied in various chronic wound healing applications.

Precisely Localized Bone Regeneration Mediated by Marine-Derived Microdroplets with Superior BMP-2 Binding Affinity.

Prompt and robust bone regeneration has been clinically achieved using supraphysiological doses of bone morphogenetic protein-2 (BMP-2) to overcome the short half-life and rapid clearance. However, uncontrolled burst release of exogenous BMP-2 causes severe complications such as heterotopic ossification and soft tissue inflammation. Therefore, numerous researches have focused on developing a new BMP-2 delivery system for a sustained release profile by immobilizing BMP-2 in various polymeric vehicles. Herein, to avoid denaturation of BMP-2 and enhance therapeutic action via localized delivery, a complex coacervate consisting of fucoidan, a marine-derived glycosaminoglycan, and poly-l-lysine (PLL) is fabricated. Superior BMP-2 binding ability and electrostatic interaction-driven engulfment enable facile and highly efficient microencapsulation of BMP-2. The microencapsulation ability of the coacervate significantly improves BMP-2 bioactivity and provides protection against antagonist and proteolysis, while allowing prolonged release. Moreover, BMP-2 containing coacervate is coated on conventional collagen sponges. The bioactivity and localized bone regenerating ability are confirmed through in vitro (human-derived stem cells), and in vivo (calvarial bone defect model) evaluations.

Establishing the transdiagnostic contextual pathways of emotional outbursts.

Emotional outbursts or temper outbursts are challenging behaviours commonly experienced by people with neurodevelopmental disorders and people who have experienced childhood adversity, which can negatively impact individuals and their families. Emotional outbursts may manifest in different situations via unique pathways distinguished by context-specific differences in the regulation and expression of emotions. Caregivers (N = 268) of young people (6-25 years) with emotional outbursts completed a bespoke caregiver-report questionnaire. Potential pathways were identified by examining the patterns of antecedents and setting events related to outbursts through factor and cluster analyses. Six contextual factors were derived from the Emotional Outburst Questionnaire. Based on these factors, the responses were classified into three clusters, which may represent potential pathways of emotional outbursts. The three clusters were characterized by the increased likelihood of outbursts: (1) across all setting events and triggers; (2) in safe setting events; (3) in unsafe setting events. These potential pathways may be related to: (1) differences in sensory processing; (2) masking of emotions in unsafe environments; (3) differences in safety perception. This framework supports a transdiagnostic account of emotional outbursts and may facilitate the development of pathway-specific intervention strategies.

Time to Functional Recovery After Laser Tonsillotomy Performed Under Local Anesthesia vs Conventional Tonsillectomy With General Anesthesia Among Adults: A Randomized Clinical Trial.

Importance: Carbon dioxide laser tonsillotomy performed under local anesthesia may be an effective and less invasive alternative than dissection tonsillectomy for treatment of tonsil-related afflictions. Objective: To compare functional recovery and symptom relief among adults undergoing tonsillectomy or tonsillotomy. Design, Setting, and Participants: This randomized clinical trial was conducted at 5 secondary and tertiary hospitals in the Netherlands from January 2018 to December 2019. Participants were 199 adult patients with an indication for surgical tonsil removal randomly assigned to either the tonsillectomy or tonsillotomy group. Interventions: For tonsillotomy, the crypts of the palatine tonsil were evaporated using a carbon dioxide laser under local anesthesia, whereas tonsillectomy consisted of total tonsil removal performed under general anesthesia. Main Outcomes and Measures: The primary outcome was time to functional recovery measured within 2 weeks after surgery assessed for a modified intention-to-treat population. Secondary outcomes were time to return to work after surgery, resolution of primary symptoms, severity of remaining symptoms, surgical complications, postoperative pain and analgesics use, and overall patient satisfaction assessed for the intention-to-treat population. Results: Of 199 patients (139 [70%] female; mean [SD] age, 29 [9] years), 98 were randomly assigned to tonsillotomy and 101 were randomly assigned to tonsillectomy. Recovery within 2 weeks after surgery was significantly shorter after tonsillotomy than after tonsillectomy (hazard ratio for recovery after tonsillectomy vs tonsillotomy, 0.3; 95% CI, 0.2-0.5). Two weeks after surgery, 72 (77%) patients in the tonsillotomy group were fully recovered compared with 26 (57%) patients in the tonsillectomy group. Time until return to work within 2 weeks was also shorter after tonsillotomy (median [IQR], 4.5 [3.0-7.0] days vs 12.0 [9.0-14.0] days; hazard ratio for return after tonsillectomy vs tonsillotomy, 0.3; 95% CI, 0.2-0.4.). Postoperative hemorrhage occurred in 2 patients (2%) in the tonsillotomy group and 8 patients (12%) in the tonsillectomy group. At 6 months after surgery, fewer patients in the tonsillectomy group (25; 35%) than in the tonsillotomy group (54; 57%) experienced persistent symptoms (difference of 22%; 95% CI, 7%-37%). Most patients with persistent symptoms in both the tonsillotomy (32 of 54; 59%) and tonsillectomy (16 of 25; 64%) groups reported mild symptoms 6 months after surgery. Conclusions and Relevance: This randomized clinical trial found that compared with tonsillectomy performed under general anesthesia, laser tonsillotomy performed under local anesthesia had a significantly shorter and less painful recovery period. A higher percentage of patients had persistent symptoms after tonsillotomy, although the intensity of these symptoms was lower than before surgery. These results suggest that laser tonsillotomy performed under local anesthesia may be a feasible alternative to conventional tonsillectomy in this population. Trial Registration: Netherlands Trial Register Identifier: NL6866 (NTR7044).

Development of a regenerative porous PLCL nerve guidance conduit with swellable hydrogel-based microgrooved surface pattern via 3D printing.

Peripheral nerve injury causes severe loss of motor and sensory functions, consequently increasing morbidity in affected patients. An autogenous nerve graft is considered the current gold standard for reconstructing nerve defects and recovering lost neurological functions; however, there are certain limitations to this method, such as limited donor nerve supply. With advances in regenerative medicine, recent research has focused on the fabrication of tissue-engineered nerve grafts as promising alternatives to the autogenous nerve grafts. In this study, we designed a nerve guidance conduit using an electrospun poly(lactide-co-ε-caprolactone) (PLCL) membrane with a visible light-crosslinked gelatin hydrogel. The PLCL nanoporous membrane with permeability served as a flexible and non-collapsible epineurium for the nerve conduit; the inner-aligned gelatin hydrogel paths were fabricated via 3D printing and a photocrosslinking system. The resultant gelatin hydrogel with microgrooved surface pattern was established as a conducting guidance path for the effective regeneration of axons and served as a reservoir that can incorporate and release bioactive molecules. From in vivo performance tests using a rat sciatic nerve defect model, our PLCL/gelatin conduit demonstrated successful axonal regeneration, remyelination capacities and facilitated functional recovery. Hence, the PLCL/gelatin conduit developed in this study is a promising substitute for autogenous nerve grafts. STATEMENT OF SIGNIFICANCE: Nerve guidance conduits (NGCs) are developed as promising recovery techniques for bridging peripheral nerve defects. However, there are still technological limitations including differences in the structures and components between natural peripheral nerve and NGCs. In this study, we designed a NGC composed of an electrospun poly(lactide-co-ε-caprolactone) (PLCL) membrane and 3D printed inner gelatin hydrogel to serve as a flexible and non-collapsible epineurium and a conducting guidance path, respectively, to mimic the fascicular structure of the peripheral nerve. In particular, in vitro cell tests clearly showed that gelatin hydrogel could guide the cells and function as a reservoir that incorporate and release nerve growth factor. From in vivo performance tests, our regenerative conduit successfully led to axonal regeneration with effective functional recovery.

[Laser treatment of the tonsils in adults on an outpatient basis]. / Poliklinische lasertonsillotomie bij volwassenen.

Tonsil complaints in adults are common. If conservative treatment fails, there is an indication for surgical removal of the tonsils. The current standard procedure, tonsillectomy under anaesthesia, is invasive, painful, and relatively often leads to complications including postoperative bleeding. There is an alternative procedure: the CO2 laser tonsillotomy under local anaesthesia. In this procedure, only the lymphatic tissue is removed. As a result, this procedure is associated with significantly less pain, shorter recovery, less postoperative bleeding, and a significant reduction in tonsil complaints.

AANG: A natural compound formula for overcoming multidrug resistance via synergistic rebalancing the TGF-ß/Smad signalling in hepatocellular carcinoma.

Cancer cells are high in heterogeneity and versatility, which can easily adapt to the external stresses via both primary and secondary resistance. Targeting of tumour microenvironment (TME) is a new approach and an ideal therapeutic strategy especially for the multidrug resistant cancer. Recently, we invented AANG, a natural compound formula containing traditional Chinese medicine (TCM) derived Smad3 inhibitor Naringenin (NG) and Smad7 activator Asiatic Acid (AA), for rebalancing TGF-ß/Smad signalling in the TME, and its implication on the multidrug resistance is still unexplored. Here, we observed that an equilibrium shift of the Smad signalling in patients with hepatocellular carcinoma (HCC), which was dramatically enhanced in the recurrent cases showing p-glycoprotein overexpression. We optimized the formula ratio and dosage of AANG that effectively inhibit the proliferation of our unique human multidrug resistant subclone R-HepG2. Mechanistically, we found that AANG not only inhibits Smad3 at post-transcriptional level, but also upregulates Smad7 at transcriptional level in a synergistic manner in vitro. More importantly, AANG markedly suppressed the growth and p-glycoprotein expression of R-HepG2 xenografts in vivo. Thus, AANG may represent a novel and safe TCM-derived natural compound formula for overcoming HCC with p-glycoprotein-mediated multidrug resistance.

USMB-shMincle: a virus-free gene therapy for blocking M1/M2 polarization of tumor-associated macrophages.

Mincle is essential for tumor-associated macrophage (TAM)-driven cancer progression and represents a potential immunotherapeutic target for cancer. Nevertheless, the lack of a specific inhibitor has largely limited its clinical translation. Here, we successfully developed a gene therapeutic strategy for silencing Mincle in a virus-free and tumor-specific manner by combining RNA interference technology with an ultrasound-microbubble-mediated gene transfer system (USMB). We identified a small hairpin RNA (shRNA) sequence shMincle that can silence not only Mincle expression but also the protumoral effector production in mouse bone marrow- and human THP-1-derived macrophages in the cancer setting in vitro. By using our well-established USMB system (USMB-shMincle), the shMincle-expressing plasmids were delivered in a tissue-specific manner into xenografts of human lung carcinoma A549 and melanoma A375 in vivo. Encouragingly, we found that USMB-shMincle effectively inhibited the protumoral phenotypes of TAMs as well as the progression of both A549 and A375 xenografts in a dose-dependent manner in mice without significant side effects. Mechanistically, we identified that USMB-shMincle markedly enhanced the anticancer M1 phenotype of TAMs in the A549 and A375 xenografts by blocking the protumoral Mincle/Syk/nuclear factor κB (NF-κB) signaling axis. Thus, USMB-shMincle may represent a clinically translatable novel and safe gene therapeutic approach for cancer treatment.

Substance P/Heparin-Conjugated PLCL Mitigate Acute Gliosis on Neural Implants and Improve Neuronal Regeneration via Recruitment of Neural Stem Cells.

The inflammatory host tissue response, characterized by gliosis and neuronal death at the neural interface, limits signal transmission and longevity of the neural probe. Substance P induces an anti-inflammatory response and neuronal regeneration and recruits endogenous stem cells. Heparin prevents nonspecific protein adsorption, suppresses the inflammatory response, and is beneficial to neuronal behavior. Poly(l-lactide-co-ε-caprolactone) (PLCL) is a soft and flexible polymer, and PLCL covalently conjugated with biomolecules has been widely used in tissue engineering. Coatings of heparin-conjugated PLCL (Hep-PLCL), substance P-conjugated PLCL (SP-PLCL), and heparin/substance P-conjugated PLCL (Hep/SP-PLCL) reduced the adhesion of astrocytes and fibroblasts and improved neuronal adhesion and neurite development compared to bare glass. The effects of these coatings are evaluated using immunohistochemistry analysis after implantation of coated stainless steel probes in rat brain for 1 week. In particular, Hep/SP-PLCL coating reduced the activation of microglia and astrocytes, the neuronal degeneration caused by inflammation, and indicated a potential for neuronal regeneration at the tissue-device interface. Suppression of the acute host tissue response by coating Hep/SP-PLCL could lead to improved functionality of the neural prosthesis.