Highly sensitive mid-infrared methane remote sensor using a deep neural network filter.

A novel mid-infrared methane remote sensor integrated on a movable platform based on a 3.291-µm interband cascade laser (ICL) and wavelength modulation spectroscopy (WMS) is proposed. A transmitting-receiving coaxial, visualized optical layout is employed to minimize laser energy loss. Using a hollow retro-reflector remotely deployed as a cooperative target, the atmospheric average methane concentration over a 100-meter optical range is measured with high sensitivity. A deep neural network (DNN) filter is used for second harmonic (2f) signal denoising to compensate for the performance shortcomings of conventional filtering. Allan deviation analysis indicated that after applying the DNN filter, the limit of detection (LOD) of methane was 86.62 ppb with an average time of 1 s, decreasing to 12.03 ppb with an average time of 229 s, which is a significant promotion compared to similar work reported. The high sensitivity and stability of the proposed sensor are shown through a 24-hour continuous monitoring experiment of atmospheric methane conducted outdoors, providing a new solution for high-sensitivity remote sensing of atmospheric methane.

Simulation evaluation of a single-photon laser methane remote sensor for leakage rate monitoring.

We propose a novel methane leakage rate remote sensor that combines a single-photon avalanche diode detector with a near-infrared 1653.7 nm low-power laser. The proposed M sequence and triangle wave signal modulation method simultaneously realizes the detection of methane leakage and target point clouds. Innovatively, the sensor's methane concentration and leakage rate quantification ability were simulated by combining the Gaussian plume diffusion model and the Risley prism. The effects of the prism rotation ratio, wind speed, leakage rate, atmospheric stability (AS), target reflectivity, signal averaging period, and concentration spatial interpolation method on leakage rate are discussed. When plume methane concentrations reduce from 10,000 to 500 ppm·m, the relative concentration bias rise from 1% to 30%, the absolute concentration bias is approximately 100 ppm·m. Two spatial concentration interpolation methods introduced leakage rate bias ranging from 6%-25%. For a low AS, the leakage rate bias under the cubic interpolation method was small (approximately 1.6%). In addition, when the initial leakage rate increased from 100 to 1,000 mg/s, the leakage rate bias was approximately 20% smaller.

Sunlight-induced degradation of COVID-19 antivirals arbidol in natural aquatic environments: Mechanisms, pathways and toxicity.

Insights into COVID-19 antivirals' environmental fate and ecological risk are urgently required due to their increasing concentrations in aquatic environments, which have rarely been studied. Herein, we first investigated the photochemical transformation and the resulting alterations in toxicity of arbidol, an antiviral drug with relatively higher toxicity. The photolysis of arbidol was rapid with a rate constant of 0.106 min-1 due to its superior ultraviolet light absorption, in which the direct photolysis was predominated with a contribution of 91.5%. Despite its substantial photolysis, only 14.45% of arbidol was mineralized after 100 min, implying that arbidol and its products might have a long-term impact on aquatic environment. It was inferred that arbidol was photolyzed mainly via the loss of thiophenol, bromine, and alkylamine, based on twelve photolytic products identified. Notably, the experimental results demonstrated that the photolysis process increased the acute toxicity of arbidol, and the toxicity prediction indicated that the ecotoxicity of two photolytic products was very high with LC50 values below 0.1 mg/L. Due to the co-effect of multiple constituents, the photolytic rate observed in wastewater treatment plant effluent and in river water was comparable to that in ultra-pure water, while it was slightly enhanced in lake water. The presence of dissolved organic matter suppressed arbidol photolysis, while NO3- exhibited a promotion effect. These results would be of great significance to assess the fate and risk of COVID-19 antivirals in natural aquatic environments.

Deep Learning-Based Dynamic Computation Task Offloading for Mobile Edge Computing Networks.

This paper investigates the computation offloading problem in mobile edge computing (MEC) networks with dynamic weighted tasks. We aim to minimize the system utility of the MEC network by jointly optimizing the offloading decision and bandwidth allocation problems. The optimization of joint offloading decisions and bandwidth allocation is formulated as a mixed-integer programming (MIP) problem. In general, the problem can be efficiently generated by deep learning-based algorithms for offloading decisions and then solved by using traditional optimization methods. However, these methods are weakly adaptive to new environments and require a large number of training samples to retrain the deep learning model once the environment changes. To overcome this weakness, in this paper, we propose a deep supervised learning-based computational offloading (DSLO) algorithm for dynamic computational tasks in MEC networks. We further introduce batch normalization to speed up the model convergence process and improve the robustness of the model. Numerical results show that DSLO only requires a few training samples and can quickly adapt to new MEC scenarios. Specifically, it can achieve 99% normalized system utility by using only four training samples per MEC scenario. Therefore, DSLO enables the fast deployment of computation offloading algorithms in future MEC networks.

Metal-Free Hydrosilylation Polymerization by Merging Photoredox and Hydrogen Atom Transfer Catalysis.

Organosilicon compounds and polymers have found wide applications as synthetic building blocks and functional materials. Hydrosilylation is a common strategy toward the synthesis of organosilicon compounds and polymers. Although transition-metal-catalyzed hydrosilylation has achieved great advances, the metal-free hydrosilylation polymerization of dienes and bis(silane)s, especially the one suitable for both electron-rich and electron-deficient dienes, is largely lacking. Herein, we report a visible-light-driven metal-free hydrosilylation polymerization of both electron-rich and electron-deficient dienes with bis(silane)s by using the organic photocatalyst and hydrogen atom transfer (HAT) catalyst. We achieved the well-controlled step-growth hydrosilylation polymerizations of the electron-rich diene and bis(silane) monomer due to the selective activation of Si-H bonds by the organic photocatalyst (4CzIPN) and the thiol polarity reversal reagent (HAT 1). For the electron-deficient dienes, hydrosilylation polymerization and self-polymerization occurred simultaneously in the presence of 4CzIPN and aceclidine (HAT 2), providing the opportunity to produce linear, hyperbranched, and network polymers by rationally tuning the concentration of electron-deficient dienes and the ratio of bis(silane)s and dienes to alter the proportion of the two polymerizations. A wide scope of bis(silane)s and dienes furnished polycarbosilanes with high molecular weight, excellent thermal stability, and tunable architectures.

Preventive effect of trimetazidine on contrast-induced nephropathy undergoing percutaneous coronary intervention in elderly moderate and high risk diabetics stratified by mehran score.

BACKGROUND: The aim of this research was to use the Mehran risk score to classify elderly diabetics with coronary heart disease to assess the preventive effect of trimetazidine on contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) in different risk population. METHODS: An uncompromised of 760 elderly diabetics that went through PCI were included in this research. The patients were first divided into three groups in the light of MRS: low-risk, moderate-risk, and high-risk group, then randomized into trimetazidine group and the control group respectively. The first endpoint was the amount of CIN, which is described as a rise in serum creatinine levels by ⩾44.2 µmol/L or ⩾25% ratio within 48 or 72 hours after medication. Second endpoint included differences in creatinine clearance rate (CrCl), blood urea nitrogen (BUN), serum creatinine (Scr), cystatin-C (Cys-C), and the incidence of major adverse events after administration. RESULTS: In the three groups, the incidence of CIN in trimetazidine and control group was 5.0% versus 4.9%(χ2 = 0.005, p > 0.05), 8.0% versus 18.0% (χ2 = 7.685, p < 0.05), 10.4% versus 27.1% (χ2 = 4.376, p < 0.05), respectively. The multivariable logistic regression result demonstrated that trimetazidine intervention was a profitable element of CIN in moderate and high-risk groups (OR = 0.294, 95% CI 0.094-0.920, p = 0.035). CONCLUSION: Our study confirmed that trimetazidine can be considered for preventive treatment of CIN occurrence in elderly diabetics with moderate and high-risk population, while there is no obvious advantage compared with hydration therapy in low-risk patients.

Trimetazidine can prevent the occurrence of contrast-induced nephropathy after percutaneous coronary intervention in elderly patients with renal insufficiency.

BACKGROUND: Contrast-induced nephropathy (CIN) has become a common cause of hospital-acquired acute kidney injury in elderly patients. Trimetazidine (TMZ) is a type of anti-ischemic drug developed in recent years, which can reduce the incidence of CIN. This study aimed to evaluate the efficacy of TMZ in the prevention of contrast-induced nephropathy in elderly patients with renal insufficiency undergoing percutaneous coronary intervention (PCI) and to explore the mechanism of action. METHODS: A total of 310 elderly patients with renal insufficiency undergoing elective PCI were enrolled and randomly assigned to a control group (n = 155, hydration only) and a TMZ group (n = 155, 20 mg thrice daily orally 24 hours before and 72 hours after PCI). The primary endpoint of the study was the incidence of CIN, which was defined as an increase of 25% or more, or an absolute increase of 0.5 mg/dL or more in serum creatinine from baseline value, at 48 to 72 hours following the exposure to contrast media (CM). RESULTS: The incidence of CIN was significantly lower in the TMZ group than that in the control group (3.2% vs. 9.7%, p = 0.021). There was no difference regarding the incidence of major adverse events during hospitalization between the TMZ group and control group (1.9% vs. 2.6%, p = 1.000). Binary logistic regression results showed that TMZ was protective factors of CIN (OR = 0.274; 95% CI: 0.089-0.847; p = 0.025). CONCLUSION: Therefore, we came to the conclusion that prophylactic administration of TMZ can prevent the occurrence of CIN in elderly patients with renal insufficiency undergoing PCI and has a certain protective effect on the renal function of patients. According to the experimental results and the mechanism of TMZ on cardiomyocytes, we speculate that TMZ increases kidney glucose metabolism, reduces fatty acid oxidation, and also has a protective effect on kidney free radical damage and ischemia-reperfusion injury.

Anion Specificity Effects on the Interfacial Aggregation Behavior of Poly(lauryl acrylate)-block-poly(N-isopropylacrylamide).

Aggregation behavior of an amphiphilic diblock copolymer poly(lauryl acrylate)-block-poly(N-isopropylacrylamide) (PLA-b-PNIPAM) on neutral aqueous subphases with different salt species and salt concentrations, as well as the structures of its Langmuir-Blodgett (LB) films, were systematically studied. The presence of NaCl or Na2SO4 in subphases makes PNIPAM chains shrink on the water surface and reduce their solubility underwater. On the contrary, the presence of NaNO3 or NaSCN makes PNIPAM chains more stretched on water and increase their solubility underwater, whose stretch degree and solubility both increase with the increase of salt concentration. Solubility of PNIPAM chains in the above subphase solutions is ranked as NaSCN ≫ NaNO3 > pure H2O > NaCl ≈ Na2SO4, which is almost consistent with the Hofmeister series except for the latter two close cases. All the initial LB films of PLA-b-PNIPAM exhibit tiny isolated circular micelles. Upon compression, the LB films in the case of pure H2O exhibit the dense mixed structures of circular micelles and wormlike aggregates. The formation of wormlike aggregates is due to connection of some adjoining cores, which is less possible in other subphase cases because of the conformation difference of PNIPAM chains.

Efficacy of alprostadil in preventing contrast-induced nephropathy in patients undergoing percutaneous coronary intervention: A multicenter prospective randomized controlled trial.

BACKGROUND: The role of alprostadil on the prevention of contrast-induced nephropathy (CIN) still remains controversial. The purpose of this study was to examine the effects of short-term alprostadil on the incidence of CIN in patients undergoing elective percutaneous coronary intervention (PCI). METHODS: A total of 480 patients with coronary heart disease undergoing PCI were enrolled in our study and randomly assigned to two groups. The control group (n = 240) was given only hydration therapy and the alprostadil group (n = 240) received intravenous administration of 20 ug/day (diluted with 100 ml normal saline) from 0.5∼1 hr before to 3 days after operation on the basis of hydration. The primary endpoint of the study was the incidence of CIN, which was defined as an increase in SCr concentration ≥ 44.2 umol/l or ≥25% above baseline within 48 hr∼72 hr after exposure of contrast media. RESULTS: The incidence of CIN was significantly lower in the alprostadil group than that in the control group (6.25% vs 11.67%, P = 0.038). Multivariate logistic regression analysis showed that alprostadil was the protective factor of CIN (OR = 0.699, 95% CI 0.542-0.902, P = 0.006). The benefits against CIN were consistent in prespecified high-risk patients with diabetes mellitus (P = 0.003). In addition, we also found that hs-CRP and blood homocysteine values after PCI were significantly lower in the alprostadil group than those in the control group. CONCLUSION: Prophylactic administration of alprostadil may prevent against CIN in coronary heart disease patients undergoing elective PCI, particularly in high-risk patients with diabetes mellitus.

Function of Novel Anti-CD19 Chimeric Antigen Receptors with Human Variable Regions Is Affected by Hinge and Transmembrane Domains.

Anti-CD19 chimeric antigen receptor (CAR) T cells have caused remissions of B cell malignancies, but problems including cytokine-mediated toxicity and short persistence of CAR T cells in vivo might limit the effectiveness of anti-CD19 CAR T cells. Anti-CD19 CARs that have been tested clinically had single-chain variable fragments (scFvs) derived from murine antibodies. We have designed and constructed novel anti-CD19 CARs containing a scFv with fully human variable regions. T cells expressing these CARs specifically recognized CD19+ target cells and carried out functions including degranulation, cytokine release, and proliferation. We compared CARs with CD28 costimulatory moieties along with hinge and transmembrane domains from either the human CD28 molecule or the human CD8α molecule. Compared with T cells expressing CARs with CD28 hinge and transmembrane domains, T cells expressing CARs with CD8α hinge and transmembrane domains produced lower levels of cytokines and exhibited lower levels of activation-induced cell death (AICD). Importantly, CARs with hinge and transmembrane regions from either CD8α or CD28 had similar abilities to eliminate established tumors in mice. In anti-CD19 CARs with CD28 costimulatory moieties, lower levels of inflammatory cytokine production and AICD are potential clinical advantages of CD8α hinge and transmembrane domains over CD28 hinge and transmembrane domains.

A simple preprocedural score for risk of contrast-induced acute kidney injury after percutaneous coronary intervention.

OBJECTIVE: To develop a simple scoring system based on preprocedural clinical features that is capable of predicting contrast-induced acute kidney injury (CI-AKI) before percutaneous coronary intervention (PCI). BACKGROUND: CI-AKI is associated with increased in-hospital morbidity and mortality, prolonged hospitalization, and long-term renal impairment. Although several scoring methods have been developed to determine risk of CI-AKI, no simple scoring method based on PCI preprocedural clinical features yet exists for Chinese patients. METHODS: A total of 2,500 Chinese patients were randomly and retrospectively assigned in a 3:2 manner to create a training and validation dataset, respectively. CI-AKI was defined as an increase of ≥25% or ≥0.5 mg/dL serum creatinine within 5 days after PCI. Preprocedural clinical variables showing independent correlation to CI-AKI were used to derive the risk score from the training dataset and then subsequently tested in the validation dataset. The odds ratios from multivariate logistic regression were used to assign a weighted integer to age ≥70 years = 4, history of myocardial infarction = 5, diabetes mellitus = 4, hypotension = 6, left ventricular ejection fraction ≤45% = 4, anemia = 3, creatinine clearance rate <60 mL/min = 7, decreased high-density lipoprotein <1 mmol/L= 3, and urgent PCI = 3. Summation of the integers represented the total risk score. RESULTS: The overall incidence of CI-AKI in the training dataset was 16.4% [246/1500; 5.4% for low (≤7) and 61.3% for very high (≥17) risk scores]. The rates of CI-AKI, 1-year dialysis, and 1-year mortality increased significantly with each group (Cochran-Armitage test of trend, P < 0.001). The risk score facilitated appropriate classification of patients with low and high risk for CI-AKI after PCI in the validation dataset (c-statistic = 0.82). CONCLUSION: Risk classification based on the most significantly correlated parameters is useful for predicting CI-AKI before contrast exposure. The simple preprocedural score showed excellent predictive ability for identifying patients at high risk of nephropathy and those with deteriorative prognosis after PCI.

Fostering emotional well-being in adolescents: the role of physical activity, emotional intelligence, and interpersonal forgiveness.

Introduction: Adolescence is considered a stress-sensitive developmental period, and the escalating and sustained pressure during this phase poses a significant threat to the mental and physical well-being of adolescents. Therefore, enhancing positive emotions in adolescents is crucial. This study aims to investigate the impact of physical activity on the emotional intelligence, interpersonal forgiveness, and positive emotions of adolescents. Methods: Using a cluster sampling method, data were collected from 500 adolescents in four schools across the Xiangxi Tujia and Miao Autonomous Prefecture of Hunan Province, China. A total of 428 valid questionnaires were collected and analyzed. The study employed AMOS v.23 to construct a structural equation model to validate the hypotheses. Results: The results indicate that physical activity significantly influences the emotional intelligence, interpersonal forgiveness, and positive emotions of adolescents. Furthermore, emotional intelligence and interpersonal forgiveness mediate the relationship between physical activity and positive emotions. Discussion: Based on these findings, collaborative efforts from government agencies, schools, and families are essential to provide robust support for adolescents' participation in physical activity, encouraging more adolescents to actively engage in sports.

Carbene-Mediated Polymer Modification Using Diazo Compounds under Photo or Thermal Activation Conditions.

Based on the characteristics of commodity polymers in large quantities and low costs, modification of existing commodity polymers emerges as the most effective approach for exploring novel materials. Nevertheless, conventional modification methods typically involve high-energy processes (e.g., high temperature, high-energy radiation), which may lead to irreversible detrimental effects on the polymers, contradicting the desired performance enhancement through modification. In this work, we propose a carbene-mediated postpolymerization modification (PPM) strategy utilizing diazo compounds. Under photochemical or thermal activation conditions, insertion of the C-H bond can be achieved without compromising the performance of polymers. These diazo compounds can be easily synthesized in just two steps and applied to all C-H-containing polymers. This practical and effective modification strategy offers new opportunities and possibilities for enhancing the value and expanding the applications of polymers.

Liposome-camouflaged iodinated mesoporous silica nanoparticles with high loading capacity, high hemodynamic stability, high biocompatibility and high radiopacity.

Due to their low osmolality and high tolerability, the highly water-soluble nonionic iodinated contrast agents, such as Ioversol (IV), are widely used as clinical agents for CT imaging. However, their clinical applications still are severely limited by the rapid renal excretion, serious adverse effects especially contrast-induced nephropathy and inefficient targetability. Various nanocarriers have demonstrated tremendous potential for achieving high imaging efficiency and low side effects. However, few nanoparticulate contrast agents can simultaneously integrate the desirable functions for imaging, including high loading capacity of iodine, high structure stability for systemic circulation, high biocompatibility and high radiopacity. Herein, we designed and prepared a kind of new radiopaque liposome-camouflaged iodinated mesoporous silica nanoparticles (OIV-MSNs@Liposomes) as contrast agents in CT imaging. Their composition, structure, morphology, biocompatibility and physicochemical properties as well as in vitro radiopacity were investigated in detail. The results indicated that OIV-MSNs@Liposomes can integrate their individual advantages of liposomes and MSNs, thus exhibiting great potential for use in the CT imaging. Considering the simple preparation process and readily available starting materials as well as enhanced biosafety and high performance in X-ray attenuation, the strategy reported here offers a versatile route to efficiently deliver highly water-soluble nonionic iodinated contrast agents for enhanced CT imaging, which are unattainable by traditional means.

A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model.

Adoptive cell transfer (ACT) using ex vivo-expanded anti-tumor T cells such as tumor-infiltrated lymphocytes or genetically engineered T cells potently eradicates established tumors. However, these two approaches possess obvious limitations. Therefore, we established a novel methodology using total tumor RNA (ttRNA) to prime dendritic cells (DC) as a platform for the ex vivo generation of anti-tumor T cells. We evaluated the antigen-specific expansion and recognition of T cells generated by the ttRNA-DC-T platform, and directly modulated the differentiation status of these ex vivo-expanded T cells with a cytokine cocktail. Furthermore, we evaluated the persistence and in vivo anti-tumor efficacy of these T cells through murine xenograft and syngeneic tumor models. During ex vivo culture, IL-2 preferentially expanded CD4 subset, while IL-7 enabled homeostatic proliferation from the original precursors. T cells tended to lose CD62L during ex vivo culture using IL-2; however, IL-12 could maintain high levels of CD62L by increasing expression on effector T cells (Tem). In addition, we validated that OVA RNA-DC only selectively expanded T cells in an antigen-specific manner. A cytokine cocktail excluding the use of IL-2 greatly increased CD62Lhigh T cells which specifically recognized tumor cells, engrafted better in a xenograft model and exhibited superior anti-tumor activities in a syngeneic intracranial model. ACT using the ex vivo ttRNA-DC-T platform in conjunction with a cytokine cocktail generated potent CD62Lhigh anti-tumor T cells and imposes a novel T cell-based therapeutic with the potential to treat brain tumors and other cancers.

Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails.

The genetic modification of CD8+ T cells using anti-tumor T-cell receptors (TCR) or chimeric antigen receptors is a promising approach for the adoptive cell therapy of patients with cancer. We previously developed a simplified method for the clinical-scale generation of central memory-like (Tcm) CD8+ T cells following transduction with lentivirus encoding anti-tumor TCR and culture in the presence of IL-2. In this study, we compared different cytokines or combinations of IL-2, IL-7, IL-12, IL-15, and IL-21 to expand genetically engineered CD8+ T cells. We demonstrated that specific cytokine combinations IL-12 plus IL-7 or IL-21 for 3 days followed by withdrawal of IL-12 yielded the phenotype of CD62L(high)CD28(high) CD127(high)CD27(high)CCR7(high), which is associated with less-differentiated T cells. Genes associated with stem cells (SOX2, NANOG, OCT4, and LIN28A), were also up-regulated by this cytokine cocktail. Moreover, the use of IL-12 plus IL-7 or IL-21 yielded CD8 T cells showing enhanced persistence in the NOD/SCID/γc-/- mouse model. This defined cytokine combination could also alter highly differentiated TIL from melanoma patients into cells with a less-differentiated phenotype. The methodology that we developed for generating a less-differentiated anti-tumor CD8+ T cells ex vivo may be ideal for the adoptive immunotherapy of cancer.

Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy.

Cluster of differentiation (CD)8(+) T cells exist as naive, central memory, and effector memory subsets, and any of these populations can be genetically engineered into tumor-reactive effector cells for adoptive immunotherapy. However, the optimal subset from which to derive effector CD8(+) T cells for patient treatments is controversial and understudied. We investigated human CD8(+) T cells and found that naive cells were not only the most abundant subset but also the population most capable of in vitro expansion and T-cell receptor transgene expression. Despite increased expansion, naive-derived cells displayed minimal effector differentiation, a quality associated with greater efficacy after cell infusion. Similarly, the markers of terminal differentiation, killer cell lectin-like receptor G1 and CD57, were expressed at lower levels in cells of naive origin. Finally, naive-derived effector cells expressed higher CD27 and retained longer telomeres, characteristics that suggest greater proliferative potential and that have been linked to greater efficacy in clinical trials. Thus, these data suggest that naive cells resist terminal differentiation, or "exhaustion," maintain high replicative potential, and therefore may be the superior subset for use in adoptive immunotherapy.

Development of a bicistronic anti-CD19/CD20 CAR construct including abrogation of unexpected nucleic acid sequence deletions.

To address CD19 loss from lymphoma after anti-CD19 chimeric antigen receptor (CAR) T cell therapy, we designed a bicistronic construct encoding an anti-CD19 CAR and an anti-CD20 CAR. We detected deletions from the expected bicistronic construct sequence in a minority of transcripts by mRNA sequencing. Loss of bicistronic construct transgene DNA was also detected. Deletions of sequence were present at much higher frequencies in transduced T cell mRNA versus gamma-retroviral vector RNA. We concluded that these deletions were caused by intramolecular template switching of the reverse transcriptase enzyme during reverse transcription of gamma-retroviral vector RNA into transgene DNA of transduced T cells. Intramolecular template switching was driven by repeated regions of highly similar nucleic acid sequence within CAR sequences. We optimized the sequence of the bicistronic CAR construct to reduce repeated regions of highly similar sequences. This optimization nearly eliminated sequence deletions. This work shows that repeated regions of highly similar nucleic acid sequence must be avoided in complex CAR constructs. We further optimized the bicistronic construct by lengthening the linker of the anti-CD20 single-chain variable fragment. This modification increased CD20-specific interleukin-2 release and reduced CD20-specific activation-induced cell death. We selected an optimized anti-CD19/CD20 bicistronic construct for clinical development.

Sustained delivery of PARP inhibitor Talazoparib for the treatment of BRCA-deficient ovarian cancer.

Background: Ovarian cancer has long been known to be the deadliest cancer associated with the female reproductive system. More than 15% of ovarian cancer patients have a defective BRCA-mediated homologous recombination repair pathway that can be therapeutically targeted with PARP inhibitors (PARPi), such as Talazoparib (TLZ). The expansion of TLZ clinical approval beyond breast cancer has been hindered due to the highly potent systemic side effects resembling chemotherapeutics. Here we report the development of a novel TLZ-loaded PLGA implant (InCeT-TLZ) that sustainedly releases TLZ directly into the peritoneal (i.p.) cavity to treat patient-mimicking BRCA-mutated metastatic ovarian cancer (mOC). Methods: InCeT-TLZ was fabricated by dissolving TLZ and PLGA in chloroform, followed by extrusion and evaporation. Drug loading and release were confirmed by HPLC. The in vivo therapeutic efficacy of InCeT-TLZ was carried out in a murine Brca2-/-p53R172H/-Pten-/- genetically engineered peritoneally mOC model. Mice with tumors were divided into four groups: PBS i.p. injection, empty implant i.p. implantation, TLZ i.p. injection, and InCeT-TLZ i.p. implantation. Body weight was recorded three times weekly as an indicator of treatment tolerance and efficacy. Mice were sacrificed when the body weight increased by 50% of the initial weight. Results: Biodegradable InCeT-TLZ administered intraperitoneally releases 66 µg of TLZ over 25 days. In vivo experimentation shows doubled survival in the InCeT-TLZ treated group compared to control, and no significant signs of toxicity were visible histologically in the surrounding peritoneal organs, indicating that the sustained and local delivery of TLZ greatly maximized therapeutic efficacy and minimized severe clinical side effects. The treated animals eventually developed resistance to PARPi therapy and were sacrificed. To explore treatments to overcome resistance, in vitro studies with TLZ sensitive and resistant ascites-derived murine cell lines were carried out and demonstrated that ATR inhibitor and PI3K inhibitor could be used in combination with the InCeT-TLZ to overcome acquired PARPi resistance. Conclusion: Compared to intraperitoneal PARPi injection, the InCeT-TLZ better inhibits tumor growth, delays the ascites formation, and prolongs the overall survival of treated mice, which could be a promising therapy option that benefits thousands of women diagnosed with ovarian cancer.

Pulsed Ultrasound-Mediated Enhancement on Transscleral and Transconjunctival Fluorescein Sodium Delivery to Rabbit Eye In Vivo.

Purpose: To investigate the efficacy and safety of pulsed ultrasound (PUS) in enhancing fluorescein sodium (NaF) transport to the rabbit eye through the transscleral and transconjunctival routes in vivo. Methods: PUS and NaF were applied onto the supratemporal sclera/conjunctiva of healthy rabbit eyes. PUS (1 MHz, 2.37 W/cm2, 30% duty cycle, 5-min application time) was performed 3 times with a 5-min interval. In the same process, NaF was administered to the eye without PUS in the control. NaF concentrations in the vitreous and retina-choroid were determined by fluorescence measurement. The safety of PUS application was assessed based on temperature and intraocular pressure measurements, clinical observations, electroretinography, histology, and Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling assay. Results: In comparison to the control, higher NaF concentrations were found in the retina-choroid following transscleral (2.45-fold) and transconjunctival (2.97-fold) PUS applications (P < 0.05). NaF concentrations in the vitreous were 3.15 and 5.86 times greater in transscleral and transconjunctival PUS applications, respectively, compared with those obtained without PUS application (P < 0.05), and NaF level in the vitreous after transconjunctival PUS application was 2.61 times that of transscleral PUS application (P < 0.05). Ocular findings were transient and mild conjunctival injection, with no other structural and functional changes in PUS-treated eyes. Conclusions: PUS treatment can improve transscleral and transconjunctival delivery of NaF efficiently and safely. Transscleral and transconjunctival PUS applications offer potential clinical benefit in increasing drug penetration to the posterior segments of the eye for the noninvasive treatment of ocular diseases.