Small molecule inhibitors targeting m6A regulators.

As the most common form of epigenetic regulation by RNA, N6 methyladenosine (m6A) modification is closely involved in physiological processes, such as growth and development, stem cell renewal and differentiation, and DNA damage response. Meanwhile, its aberrant expression in cancer tissues promotes the development of malignant tumors, as well as plays important roles in proliferation, metastasis, drug resistance, immunity and prognosis. This close association between m6A and cancers has garnered substantial attention in recent years. An increasing number of small molecules have emerged as potential agents to target m6A regulators for cancer treatment. These molecules target the epigenetic level, enabling precise intervention in RNA modifications and efficiently disrupting the survival mechanisms of tumor cells, thus paving the way for novel approaches in cancer treatment. However, there is currently a lack of a comprehensive review on small molecules targeting m6A regulators for anti-tumor. Here, we have comprehensively summarized the classification and functions of m6A regulators, elucidating their interactions with the proliferation, metastasis, drug resistance, and immune responses in common cancers. Furthermore, we have provided a comprehensive overview on the development, mode of action, pharmacology and structure-activity relationships of small molecules targeting m6A regulators. Our aim is to offer insights for subsequent drug design and optimization, while also providing an outlook on future prospects for small molecule development targeting m6A.

Solid-Emission-Tunable Squaraine with Thermal-Promoted Aggregate-State Transitions for Fast Thermal History Sensing.

Determining thermal history is crucial in many industrial processes, but reliable and sensitive organic thermal history indicators are currently absent. Herein, we report on the development of a squaraine-based fluorescent molecule, DPEA-SQ, for the detection of thermal exposure histories up to 436 K. DPEA-SQ forms multiple single crystals (DPEA-SQ-I, DPEA-SQ-II, and DPEA-SQ-III) with different conformations and aggregate-state packing modes, contributing to their different fluorescence wavelengths, lifetimes, and efficiencies. Interestingly, DPEA-SQ-I and DPEA-SQ-III undergo aggregate-state structural transitions to form the thermodynamically more stable DPEA-SQ-II, which are accompanied by changes in their fluorescence. By taking advantage of similar aggregate-state structural transformations during heating, a high-temperature thermal exposure history of up to 436 K is recorded and reflected by their fluorescence. To demonstrate the potential practical applications of DPEA-SQ, a DPEA-SQ-Powder/PDMS film is prepared and coated on an electric circuit board, which enables real-time monitoring of localized overheating by the naked eye. Additionally, the fluorescence peaks of DPEA-SQ-Powder and DPEA-SQ-Powder/PDMS films remain unchanged after storage at 373 K for 52 days, demonstrating high aggregate-state stability. The fast and reliable responses of this system make it an excellent candidate for the detection of overtemperature traces in electronic components and circuit diagnosis.

Mammalian IRE1α dynamically and functionally coalesces with stress granules.

Upon endoplasmic reticulum (ER) stress, activation of the ER-resident transmembrane protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) initiates a key branch of the unfolded protein response (UPR) through unconventional splicing generation of the transcription factor X-box-binding protein 1 (XBP1s). Activated IRE1 can form large clusters/foci, whose exact dynamic architectures and functional properties remain largely elusive. Here we report that, in mammalian cells, formation of IRE1α clusters is an ER membrane-bound phase separation event that is coupled to the assembly of stress granules (SGs). In response to different stressors, IRE1α clusters are dynamically tethered to SGs at the ER. The cytosolic linker portion of IRE1α possesses intrinsically disordered regions and is essential for its condensation with SGs. Furthermore, disruption of SG assembly abolishes IRE1α clustering and compromises XBP1 mRNA splicing, and such IRE1α-SG coalescence engenders enrichment of the biochemical components of the pro-survival IRE1α-XBP1 pathway during ER stress. Our findings unravel a phase transition mechanism for the spatiotemporal assembly of IRE1α-SG condensates to establish a more efficient IRE1α machinery, thus enabling higher stress-handling capacity.

Mobilizing endogenous neuroprotection: the mechanism of the protective effect of acupuncture on the brain after stroke.

Given its high morbidity, disability, and mortality rates, ischemic stroke (IS) is a severe disease posing a substantial public health threat. Although early thrombolytic therapy is effective in IS treatment, the limited time frame for its administration presents a formidable challenge. Upon occurrence, IS triggers an ischemic cascade response, inducing the brain to generate endogenous protective mechanisms against excitotoxicity and inflammation, among other pathological processes. Stroke patients often experience limited recovery stages. As a result, activating their innate self-protective capacity [endogenous brain protection (EBP)] is essential for neurological function recovery. Acupuncture has exhibited clinical efficacy in cerebral ischemic stroke (CIS) treatment by promoting the human body's self-preservation and "Zheng Qi" (a term in traditional Chinese medicine (TCM) describing positive capabilities such as self-immunity, self-recovery, and disease prevention). According to research, acupuncture can modulate astrocyte activity, decrease oxidative stress (OS), and protect neurons by inhibiting excitotoxicity, inflammation, and apoptosis via activating endogenous protective mechanisms within the brain. Furthermore, acupuncture was found to modulate microglia transformation, thereby reducing inflammation and autoimmune responses, as well as promoting blood flow restoration by regulating the vasculature or the blood-brain barrier (BBB). However, the precise mechanism underlying these processes remains unclear. Consequently, this review aims to shed light on the potential acupuncture-induced endogenous neuroprotective mechanisms by critically examining experimental evidence on the preventive and therapeutic effects exerted by acupuncture on CIS. This review offers a theoretical foundation for acupuncture-based stroke treatment.

A tunable ultra-broadband and ultra-high sensitivity far-infrared metamaterial absorber based on VO2 and graphene.

We proposed a far-infrared tunable metamaterial absorber using vanadium dioxide (VO2) and graphene as controlling materials. The properties of the absorber are investigated theoretically using the finite-difference time-domain (FDTD) technique. It was found that when the Fermi energy level of graphene is fixed at zero, VO2 is in the insulated state, and the metasurface exhibits far-infrared broadband absorption performance, with absorptance exceeding 90% in the wavelength range of 12.6 µm to 23.2 µm. In addition, by elevating the Fermi energy level of graphene, the absorption bandwidth of the device is expanded continuously. When the VO2 is in the metallic state, the device can flexibly transform into a far-infrared narrowband absorber. The device also has the advantage of being insensitive to changes in polarization and incident angle. The origin of the absorption and the tuning principle of the device were analyzed and verified successfully by using an equivalent circuit model (ECM). Besides, we also studied the refraction index sensing characteristics of the absorber. Surprisingly, the absorber exhibits excellent sensing characteristics, and its sensitivity (S) reaches 14.108 µm per RIU and the figure of merit (FOM) is 6.13 per RIU.

Protein tyrosine phosphatases: emerging role in cancer therapy resistance.

BACKGROUND: Tyrosine phosphorylation of intracellular proteins is a post-translational modification that plays a regulatory role in signal transduction during cellular events. Dephosphorylation of signal transduction proteins caused by protein tyrosine phosphatases (PTPs) contributed their role as a convergent node to mediate cross-talk between signaling pathways. In the context of cancer, PTP-mediated pathways have been identified as signaling hubs that enabled cancer cells to mitigate stress induced by clinical therapy. This is achieved by the promotion of constitutive activation of growth-stimulatory signaling pathways or modulation of the immune-suppressive tumor microenvironment. Preclinical evidences suggested that anticancer drugs will release their greatest therapeutic potency when combined with PTP inhibitors, reversing drug resistance that was responsible for clinical failures during cancer therapy. AREAS COVERED: This review aimed to elaborate recent insights that supported the involvement of PTP-mediated pathways in the development of resistance to targeted therapy and immune-checkpoint therapy. EXPERT OPINION: This review proposed the notion of PTP inhibition in anticancer combination therapy as a potential strategy in clinic to achieve long-term tumor regression. Ongoing clinical trials are currently underway to assess the safety and efficacy of combination therapy in advanced-stage tumors.

Association of autoimmune and allergic diseases with senile cataract: a bidirectional two-sample Mendelian randomization study.

Background: Many observational studies have been reported that patients with autoimmune or allergic diseases seem to have a higher risk of developing senile cataract, but the views are not consistent. In order to minimize the influence of reverse causality and potential confounding factors, we performed Mendelian Randomization (MR) analysis to investigate the genetic causal associations between autoimmune, allergic diseases and senile cataract. Methods: Single nucleotide polymorphisms associated with ten common autoimmune and allergic diseases were obtained from the IEU Open genome-wide association studies (GWAS) database. Summary-level GWAS statistics for clinically diagnosed senile cataract were obtained from the FinnGen research project GWAS, which consisted of 59,522 individuals with senile cataracts and 312,864 control individuals. MR analysis was conducted using mainly inverse variance weighted (IVW) method and further sensitivity analysis was performed to test robustness. Results: As for ten diseases, IVW results confirmed that type 1 diabetes (OR = 1.06; 95% CI = 1.05-1.08; p = 2.24×10-12), rheumatoid arthritis (OR = 1.05; 95% CI = 1.02-1.08; p = 1.83×10-4), hypothyroidism (OR = 2.4; 95% CI = 1.42-4.06; p = 1.12×10-3), systemic lupus erythematosus (OR = 1.02; 95% CI = 1.01-1.03; p = 2.27×10-3), asthma (OR = 1.02; 95% CI = 1.01-1.03; p = 1.2×10-3) and allergic rhinitis (OR = 1.07; 95% CI = 1.02-1.11; p = 2.15×10-3) were correlated with the risk of senile cataract. Celiac disease (OR = 1.04; 95% CI = 1.01-1.08; P = 0.0437) and atopic dermatitis (OR = 1.05; 95% CI = 1.01-1.10; P = 0.0426) exhibited a suggestive connection with senile cataract after Bonferroni correction. These associations are consistent across weighted median and MR Egger methods, with similar causal estimates in direction and magnitude. Sensitivity analysis further proved that these associations were reliable. Conclusions: The results of the MR analysis showed that there were causal relationships between type 1 diabetes, rheumatoid arthritis, hypothyroidism, systemic lupus erythematosus, asthma, allergic rhinitis and senile cataract. To clarify the possible role of autoimmune and allergy in the pathophysiology of senile cataract, further studies are needed.

Structure-Guided Discovery and Preclinical Assessment of Novel (Thiophen-3-yl)aminopyrimidine Derivatives as Potent ERK1/2 Inhibitors.

The RAS-RAF-MEK-ERK signaling cascade is abnormally activated in various tumors, playing a crucial role in mediating tumor progression. As the key component at the terminal stage of this cascade, ERK1/2 emerges as a potential antitumor target and offers a promising therapeutic strategy for tumors harboring BRAF or RAS mutations. Here, we identified 36c with a (thiophen-3-yl)aminopyrimidine scaffold as a potent ERK1/2 inhibitor through structure-guided optimization for hit 18. In preclinical studies, 36c showed powerful ERK1/2 inhibitory activities (ERK1/2 IC50 = 0.11/0.08 nM) and potent antitumor efficacy both in vitro and in vivo against triple-negative breast cancer and colorectal cancer models harboring BRAF and RAS mutations. 36c could directly inhibit ERK1/2, significantly block the phosphorylation expression of their downstream substrates p90RSK and c-Myc, and induce cell apoptosis and incomplete autophagy-related cell death. Taken together, this work provides a promising ERK1/2 lead compound for multiple tumor-treatment drug discovery.

Aggressive vertebral hemangiomas contain no adipose tissue resulting in thoracic spine kyphosis: A case report.

RATIONALE: Aggressive vertebral hemangiomas (AVHs) destroy continuous vertebral bodies and intervertebral discs and resulting in spinal kyphosis is extremely rare. The very aggressive behavior was attributable to its significant vascular component and contained no adipose tissue. PATIENT CONCERNS: We report a case of thoracic spine kyphosis of AVHs with multiple vertebral bodies and intervertebral disc destruction in a 45-year-old woman. DIAGNOSES: Based on the imaging studies, the patient underwent surgical removal of this lesion and spinal reconstruction. Histopathology consistent with vertebral hemangioma and contained no adipose. INTERVENTIONS: The patient underwent surgical removal of the lesion and spinal reconstruction. After subperiosteal dissection of the paraspinal muscles and exposure of the laminae, the laminae of the T5-7 vertebrae were removed and exposing the lesion. The lesion was soft and showed cystic changes, completely curetted and autogenous bone was implanted. Vertebroplasty was performed through T3-T9 pedicles bilaterally. Pedicle screw fixation was performed for segmental fixation and fusion. OUTCOMES: After 9 days of operation, the incision healed cleanly and free of pain. She was discharged in good general condition. The patient remained asymptomatic after follow-up 6 months of postoperative. LESSONS: AVHs destroy multiple vertebral bodies and intervertebral discs and resulting in spinal kyphosis is extremely rare.

Clinical practice guideline for acupuncture and moxibustion: Female urinary incontinence.

Urinary incontinence (UI) is a common problem worldwide. It has a major impact on physical and social activities and interpersonal relationships. UI is common in women, but is under-reported and under-treated. It affects the quality of life of female patients severely. Acupuncture and moxibustion have been proposed as potentially effective interventions for female UI. Hence, for the benefit of acupuncture practitioners around the world, the World Federation of Acupuncture-moxibustion Societies initiated a project to develop a clinical practice guideline (CPG) for the use of acupuncture and moxibustion to treat female UI. This CPG was developed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, referring to the principles of the World Health Organization Handbook for Guideline Development. During the development of the CPG, the guideline development group (GDG) played an important role. The clinical questions, recommendations and therapeutic protocols were all formulated by GDG using the modified Delphi method. This CPG contains ten recommendations about the use of acupuncture and moxibustion interventions for ten clinical questions, which include nine conditional recommendations for the intervention and one conditional recommendation for either the intervention or the comparison. This CPG also provides one protocol for conventional filiform needle therapy, two therapy protocols for deep needling stimulation on lumbosacral acupoints, and four moxibustion therapy protocols, based on the protocols presented in randomized controlled trials reviewed by the GDG. Please cite this article as: Yang C, Wang SZ, Chen S, Du S, Wang GQ, Guo W, et al. Clinical practice guideline for acupuncture and moxibustion: Female urinary incontinence. J Integr Med. 2024; Epub ahead of print.

Synergistic antibacterial and antifouling wound dressings: Integration of photothermal-activated no release and zwitterionic surface modification.

Addressing the pervasive issue of bacteria and biofilm infections is crucial in the development of advanced antifouling wound dressings. In this study, a novel wound healing treatment using sulfobetaine (SBMA) decorated electrospun fibrous membrane based on polycaprolactone (PCL)/nitric oxide (NO) donors was developed. The fabrication involved a dual strategy, first integrating NO donors into mesoporous polydopamine (MPDA) and complexed with PCL/PEI to electrospin nanofibers. The fibrous membrane exhibited a potent antibacterial response upon irradiation at 808 nm, owing to a combination of NO and photothermal effect that effectively targets bacteria and disrupts biofilms. Surface functionalization of the membrane with PEI allowed for the attachment of SBMA via Michael addition, fabricating a zwitterionic surface, which significantly hinders protein adsorption and reduces biofilm formation on the wound dressing. In vitro and in vivo assessments confirmed the rapid bactericidal capabilities and its efficacy in biofilm eradication. Combining photothermal activity, targeted NO release and antifouling surface, this multifaceted wound dressing addresses key challenges in bacterial infection management and biofilm eradication, promoting efficient wound healing.

Investigation on Mechanism of Microstructure Evolution during Multi-Process Hot Forming of GH4169 Superalloy Forging.

Typically, in the manufacturing of GH4169 superalloy forgings, the multi-process hot forming that consists of pre-deformation, heat treatment and final deformation is required. This study focuses on the microstructural evolution throughout hot working processes. Considering that δ phase can promote nucleation and limit the growth of grains, a process route was designed, including pre-deformation, aging treatment (AT) to precipitate sufficient δ phases, high temperature holding (HTH) to uniformly heat the forging, and final deformation. The results show that the uneven strain distribution after pre-deformation has a significant impact on the subsequent refinement of the grain microstructure due to the complex coupling relationship between the evolution of the δ phase and recrystallization behavior. After the final deformation, the fine-grain microstructure with short rod-like δ phases as boundaries is easy to form in the region with a large strain of the pre-forging. However, necklace-like mixed grain microstructure is formed in the region with a small strain of the pre-forging. In addition, when the microstructure before final deformation consists of mixed grains, dynamic recrystallization (DRX) nucleation behavior preferentially depends on kernel average misorientation (KAM) values. A large KAM can promote the formation of DRX nuclei. When the KAM values are close, a smaller average grain size of mixed-grain microstructure is more conductive to promote the DRX nucleation. Finally, the interaction mechanisms between δ phase and DRX nucleation are revealed.

Clinical practice guideline for acupuncture and moxibustion: Allergic rhinitis.

Acupuncture is one of the most effective complementary therapies for allergic rhinitis (AR) and has been recommended by several clinical practice guidelines (CPGs) for AR. However, these CPGs mentioned acupuncture without making recommendations for clinical implementation and therapeutic protocols, therefore limiting the applicability of acupuncture therapies for AR. Hence, for the benefit of acupuncture practitioners around the world, the World Federation of Acupuncture-moxibustion Societies have initiated a project to develop the CPG for the use of acupuncture and moxibustion to treat AR. This CPG was developed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, referring to the principles of the World Health Organization Handbook for Guideline Development. During the development of the CPG, the guideline development group (GDG) played an important role. The clinical questions, recommendations and therapeutic protocols were all formulated by the GDG using the modified Delphi method. The CPG contains recommendations for 15 clinical questions about the use of acupuncture and moxibustion interventions. These include one strong recommendation for the intervention based on high-quality evidence, three conditional recommendations for either the intervention or standard care, and 11 conditional recommendations for the intervention based on very low quality of evidence. The CPG also provides one filiform needle acupuncture protocol and five moxibustion protocols extracted based on the protocols presented in randomized controlled trials reviewed by the GDG. Please cite this article as: Du SH, Chen S, Wang SZ, Wang GQ, Du S, Guo W, Xie XL, Peng BH, Yang C, Zhao JP. Clinical practice guideline for acupuncture and moxibustion: Allergic rhinitis. J Integr Med. 2024; Epub ahead of print.

Discovery of a novel small-molecule activator of SIRT3 that inhibits cell proliferation and migration by apoptosis and autophagy-dependent cell death pathways in colorectal cancer.

Colorectal cancer (CRC) is well known as a prevalent malignancy affecting the digestive tract, yet its precise etiological determinants remain to be elusive. Accordingly, identifying specific molecular targets for colorectal cancer and predicting potential malignant tumor behavior are potential strategies for therapeutic interventions. Of note, apoptosis (type I programmed cell death) has been widely reported to play a pivotal role in tumorigenesis by exerting a suppressive effect on cancer development. Moreover, autophagy-dependent cell death (type II programmed cell death) has been implicated in different types of human cancers. Thus, investigating the molecular mechanisms underlying apoptosis and autophagy-dependent cell death is paramount in treatment modalities of colorectal cancer. In this study, we uncovered that a new small-molecule activator of SIRT3, named MY-13, triggered both autophagy-dependent cell death and apoptosis by modulating the SIRT3/Hsp90/AKT signaling pathway. Consequently, this compound inhibited tumor cell proliferation and migration in RKO and HCT-116 cell lines. Moreover, we further demonstrated that the small-molecule activator significantly suppressed tumor growth in vivo. In conclusion, these findings demonstrate that the novel small-molecule activator of SIRT3 may hold a therapeutic potential as a drug candidate in colorectal cancer.

Natural products and derivatives for breast cancer treatment: From drug discovery to molecular mechanism.

BACKGROUND: Breast cancer stands as the most common malignancy among women globally and a leading cause of cancer-related mortality. Conventional treatments, such as surgery, hormone therapy, radiotherapy, chemotherapy, and small-molecule targeted therapy, often fall short of addressing the complexity and heterogeneity of certain breast cancer subtypes, leading to drug resistance and metastatic progression. Thus, the search for novel therapeutic targets and agents is imperative. Given their low toxicity and abundant variety, natural products and their derivatives are increasingly considered valuable sources for small-molecule anticancer drugs. PURPOSE: This review aims to elucidate the pharmacological impacts and underlying mechanisms of active compounds found in select natural products and their derivatives, primarily focusing on breast cancer treatment. It intends to underscore the potential of these substances in combating breast cancer and guide future research directions for the development of natural product-based therapeutics. METHODS: We conducted comprehensive searches in electronic databases such as PubMed, Web of Science, and Scopus until October 2023, using keywords such as 'breast cancer', 'natural products', 'derivatives', 'mechanism', 'signaling pathways', and various keyword combinations. RESULTS: The review presents a spectrum of phytochemicals, including but not limited to flavonoids, polyphenols, and alkaloids, and examines their actions in various animal and cellular models of breast cancer. The anticancer effects of these natural products and derivatives are manifested through diverse mechanisms, including induction of cell death via apoptosis and autophagy, and suppression of tumor angiogenesis. CONCLUSION: An increasing array of natural products and their derivatives are proving effective against breast cancer. Future therapeutic strategies can benefit from strategic enhancement of the anticancer properties of natural compounds, optimization for targeted action, improved bioavailability, and minimized side effects. The forthcoming research on natural products should prioritize these facets to maximize their therapeutic potential.

Excavating important nodes in complex networks based on the heat conduction model.

Analyzing the important nodes of complex systems by complex network theory can effectively solve the scientific bottlenecks in various aspects of these systems, and how to excavate important nodes has become a hot topic in complex network research. This paper proposes an algorithm for excavating important nodes based on the heat conduction model (HCM), which measures the importance of nodes by their output capacity. The number and importance of a node's neighbors are first used to determine its own capacity, its output capacity is then calculated based on the HCM while considering the network density, distance between nodes, and degree density of other nodes. The importance of the node is finally measured by the magnitude of the output capacity. The similarity experiments of node importance, sorting and comparison experiments of important nodes, and capability experiments of multi-node infection are conducted in nine real networks using the Susceptible-Infected-Removed model as the evaluation criteria. Further, capability experiments of multi-node infection are conducted using the Independent cascade model. The effectiveness of the HCM is demonstrated through a comparison with eight other algorithms for excavating important nodes.

Independence Threat or Interdependence Threat? The Focusing Effect on Social or Physical Threat Modulates Brain Activity.

OBJECTIVE: The neural basis of threat perception has mostly been examined separately for social or physical threats. However, most of the threats encountered in everyday life are complex. The features of interactions between social and physiological threats under different attentional conditions are unclear. METHOD: The present study explores this issue using an attention-guided paradigm based on ERP techniques. The screen displays social threats (face threats) and physical threats (action threats), instructing participants to concentrate on only one type of threat, thereby exploring brain activation characteristics. RESULTS: It was found that action threats did not affect the processing of face threats in the face-attention condition, and electrophysiological evidence from the brain suggests a comparable situation to that when processing face threats alone, with higher amplitudes of the N170 and EPN (Early Posterior Negativity) components of anger than neutral emotions. However, when focusing on the action-attention condition, the brain was affected by face threats, as evidenced by a greater N190 elicited by stimuli containing threatening emotions, regardless of whether the action was threatening or not. This trend was also reflected in EPN. CONCLUSIONS: The current study reveals important similarities and differences between physical and social threats, suggesting that the brain has a greater processing advantage for social threats.

Snake-shaped ePTFE nasal tip graft combined with conchal cartilage in Asian rhinoplasty: a retrospective cohort study.

BACKGROUND: Lacking a nasal tip projection is a common deformity of Asian nasals. Various commonly used nasal tip grafts require dissecting septal perichondrium, most of them are autologous cartilage with a nonintegrated design. A snake-shaped expanded polytetrafluoroethylene (ePTFE) nasal tip graft is an integrated, stable tip graft without any additional assembly and splicing, conforming to the nasal anatomy characteristics of Asians. METHOD: A retrospective study was performed on Asian patients who underwent rhinoplasty in the nasal tip at Peking University Third Hospital from 2015 to 2022. Nasal tip grafts were categorized into three groups: snake-shaped ePTFE combined with conchal cartilage (n = 15), only costal cartilage (n = 25), and only conchal cartilage (n = 17). Patients were excluded if their rhinoplasty did not involve any of the grafts above. Visual Analogue Scale, FACE-Q Nose, FACE-Q Nostril, Nasal Obstruction Symptom Evaluation scale, and Rhinoplasty Outcome Evaluation scale were used to evaluate the preoperative and postoperative results. RESULTS: Fifty-three (93.0%) cases had low nasal dorsum and 46 (80.7%) cases had short nose. There was no significant difference in complication rates among the three groups. The difference between preoperative and postoperative scale scores was statistically significant among the three groups (p < 0.05). Score improvements, including all scales, were the highest in the costal cartilage group and lowest in the conchal cartilage group. CONCLUSIONS: Snake-shaped ePTFE nasal tip grafts can be an effective integrated alternative that provides long-term safety and efficacy compared with traditional autogenous implants (conchal and costal cartilages).

A fully validated LC­MS/MS method for quantifying bevacizumab in plasma samples from patients with NSCLC and its implications in therapeutic drug monitoring.

Given the increasing use of bevacizumab in combinatorial drug therapy for a multitude of different cancer types, there is a need for therapeutic drug monitoring to analyze the possible correlation between drug trough concentration, and therapeutic effect and adverse reactions. An ultra-performance liquid chromatography tandem-mass spectrometry method was then developed and validated to determine bevacizumab levels in human plasma samples. Chromatographic separation was achieved on a Shimadzu InertSustainBio C18 HP column, whereas subsequent mass spectrometric analysis was performed using a Shimadzu 8050CL triple quadrupole mass spectrometer equipped with an electro-spray ionization source in the positive ion mode. In total, three multiple reaction monitoring transitions of each of the surrogate peptides were chosen with 'FTFSLDTSK' applied as the quantification peptide whereas 'VLIYFTSSLHSGVPSR' and 'STAYLQMNSLR' were designated as the verification peptides using the Skyline software. This analytical method was then fully validated, with specificity, linearity, lower limit of quantitation, accuracy, precision, stability, matrix effect and recovery calculated. The linearity of this method was developed to be within the concentration range 5-400 µg/ml for bevacizumab in human plasma. Subsequently, eight patients with non-small cell lung cancer (NSCLC) were recruited and injected with bevacizumab over three periods of treatment to analyze their steady-state trough concentration and differences. To conclude, the results of the present study suggest that bevacizumab can be monitored in a therapeutic setting in patients with NSCLC.

A TLR4-Targeting Bioactive Peptide Hydrogel to Regulate Immune-Microenvironment for Diabetic Wound Repair.

Persistent inflammation and disrupted immunoregulation are critical factors in impeding diabetic wound healing. While immunoregulatory hydrogel dressings hold significant promise for clinical applications in diabetic wound healing, the current application often demands intricate interventions and high-cost treatments involving cytokines and cell therapies. The development of single component immunoregulatory hydrogels remains a complex challenge. To address this issue, an active peptide hydrogel with immunoregulatory properties targeting the TLR4/NF-kB pathway, aiming to promote rapid diabetic wound healing, is engineered. The hydrogel sequence comprises naphthalene derivative, phenylalanine, and glycine to modulate hydrophilic/hydrophobic characteristics. The amino group on arginine contributes to tissue adhesion and regulation of intermolecular forces, ultimately yielding stable gels. The results underscore the formation of the peptide hydrogel (NFA) via the physical crosslinking of self-assembled nanofibers in water, thereby affording both excellent injectability and tissue adhesion. Notably, NFA demonstrates significant potential in promoting wound healing in a mouse model with full-thickness wounds by regulating macrophage responses in the inflammatory microenvironment through the TLR4/NF-kB pathway.