Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages.

Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.

Identification of circRNAs and circRNA-mRNA network of Epinephelus coioides during Singapore grouper iridovirus infection.

Circular RNA (circRNA), one of the important non-coding RNA molecules with a closed-loop structure, plays a key regulatory role in cell processing. In this study, circRNAs of Epinephelus coioides, an important marine cultured fish in China, were isolated and characterized, and the network of circRNAs and mRNA was explored during Singapore grouper iridovirus (SGIV) infection, one of the most important double stranded DNA virus pathogens of marine fish. 10 g of raw data was obtained by high-throughput sequencing, and 2599 circRNAs were classified. During SGIV infection, 123 and 37 circRNAs occurred differential expression in spleen and spleen cells, indicating that circRNAs would be involved in the viral infection. GO annotation and KEGG demonstrated that circRNAs could target E. coioides genes to regulate cell activity and the activation of immune factors. The results provide some insights into the circRNAs mediated immune regulatory network during bony fish virus infection.

Self-Enhanced Electrochemiluminescence Imaging System Based on the Accelerated Generation of ROS under Ultrasound.

Electrochemiluminescence (ECL) imaging, as an optical technology, has been developed at full tilt in the field of life science and nanomaterials. However, the relatively low ECL intensity or the high co-reactant concentration needed in the electrochemical reaction blocks its practical application. Here, we developed an ECL imaging system based on the rGO-TiO2-x composite material, where the co-reactant, reactive oxygen species (ROS), is generated in situ under the synergetic effect of of ultrasound (US) and electric irradiation. The rGO-TiO2-x composites facilitate the separation of electron (e-) and hole (h+) pairs and inhibit recombination triggered by external US irradiation due to the high electroconductivity of rGO and oxygen-deficient structures of TiO2, thus significantly boosting ROS generation. Furthermore, the increased defects on rGO accelerate the electron transfer rate, improving the electrocatalytic performance of the composite and forming more ROS. This high ultrasonic-electric synergistic efficacy is demonstrated through the enhancement of photon emission. Compared with the luminescence intensity triggered by US irradiation and electric field, an enhancement of ∼20-fold and 10-fold of the US combined with electric field-triggered emission is observed from this composite. Under the optimized conditions, using dopamine (DA) as a model target, the sensitivity of the US combined ECL strategy for detection of DA is two orders of magnitude higher than that of the ECL method. The successful detection of DA at low concentrations makes us believe that this strategy provides the possibility of applying ECL imaging for cellular single-molecule analysis and cancer therapy.

Pathogenetic and Therapeutic Role of Gut Microbiome in Immunoglobin A Nephropathy.

Immunoglobulin A nephropathy (IgAN) is a common primary glomerulonephritis, which is mainly characterized by excessive IgA deposition in the glomerular mesangial area. Although exploring the pathogenesis of IgAN and improving the treatment strategies continuously, the exact pathogenesis of IgAN remains unclear and the disease still leads to high mortality. Recently, emerging evidence has demonstrated that dysregulated intestinal mucosal immunity and gut microbiome imbalance may play a combined role in the development and progression of IgAN. It has been suggested that reconstructing the intestinal microenvironment and maintaining the stability and metabolic balance of gut microbiome are expected to become new treatment strategies. Meanwhile, inhibiting mucosa-associated lymphoid tissue (MALT) controlled by the gut microbiome may become an alternative treatment, especially used to reduce the excessive production of IgA in IgAN. In this review, we summarized the correlation between gut microbiome and the pathogenesis of IgAN, as well as the therapeutic potential of gut microbiome in this disease.

Recent progress of metal nanoclusters in electrochemiluminescence.

Metal nanoclusters (MeNCs), composed of a few to hundreds of metal atoms and appropriate surface ligands, have attracted extensive interest in the electrochemiluminescence (ECL) realm owing to their molecule-like optical, electronic, and physicochemical attributes and are strongly anticipated for discrete energy levels, fascinating electrocatalytic activity, and good biocompatibility. Over the past decade, huge efforts have been devoted to the synthesis, properties, and application research of ECL-related MeNCs, and this field is still a subject of heightened concern. Therefore, this perspective aims to provide a comprehensive overview of the recent advances of MeNCs in the ECL domain, mainly covering the emerged ECL available MeNCs, unique chemical and optical properties, and the general ECL mechanisms. Synthesis strategies for desirable ECL performance are further highlighted, and the resulting ECL sensing applications utilizing MeNCs as luminophores, quenchers, and substrates are discussed systematically. Finally, we anticipate the future prospects and challenges in the development of this area.

[Correlation between chirp auditory brainstem response and behavioral hearing threshold in children].

OBJECTIVE: To investigate the correlation between thresholds in the chirp-ABR and behavior audiogram in order to find out if it is possible to be used as an clinical application of the chirp-ABR in estimating hearing sensitivity. METHODS: Twenty-two cases with hearing loss or normal hearing were enrolled in the study. The behavior audiogram and the response thresholds of chirp ABR (including chirp ABR, L-chirp ABR and U-chirp ABR) were obtained from 35 ears. RESULTS: Twenty-two cases were of both genders. The age was between 3.3- 6.5-years-old with the average age of 4.8-years-old. Divided by the degree of hearing loss, in the 35 ears, there were 6 with normal hearing, 2 with slightly hearing loss, 4 with moderate hearing loss, 10 with severe hearing loss and 13 with profound hearing loss. The Pearson correlation coefficients were 0.939, 0.900 and 0.930, respectively, which got from the data between the average of 0.5 - 4 kHz and chirp ABR respond threshold, 0.5 kHz and L-chirp ABR, and the average of 1 - 4 kHz and U-chirp ABR. CONCLUSION: As an objective test, the response threshold of chirp-ABR and the behavior audiogram were a highly correlated with each other, but more application in more subjects is needed.

[Evaluation and analysis of auditory function and its clinical characteristics in low birth weight premature infants.].

OBJECTIVE: To investigate and analyze dynamic changes of auditory function in premature babies with fetal age of less than 37 weeks who were categorized into different birth weight groups and to detect abnormalities of auditory function in these babies and to describe the early development patterns of auditory function in infancy. METHODS: Total of 252 subjects (504 ears) from neonatal ward, neonatal intensive care unit and auditory clinic in Guangzhou Children Hospital, whose fetal age were less than 37 weeks, were included in our study and received auditory function evaluation from January 2004 to February 2008. To investigate the correlation between birth weight and development and abnormality of auditory function in premature babies, all subjects were divided into four groups according to birth weight: 2.5 kg. Each group was further categorized by subject's age on first auditory function evaluation in 0 - 3 months (include 3 months), 3 - 6 months (include 6 months) and above 6 months, respectively. Subjects who were evaluated more than once in different age frame would be grouped into multiple evaluation subgroups. All subjects underwent one or more objective auditory examinations including auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), tympanometry and acoustic stapedius reflex. RESULTS: A tendency of decreased wave V threshold of ABR was seen as birth weight increased, while the percentage of subjects with ABR wave V threshold

[Audiological characteristics and localization of lesions in children with retrocochlear auditory nerve impairment].

OBJECTIVE: To explore the clinic characteristics, audiological characteristics and location of lesions in children with retrocochlear auditory nerve impairment which, including auditory neuropathy characterized by severely abnormal results of ABR and normal results of DPOAE. METHODS: Between 2002 and 2006, eighty-six cases (165 ears) with severely abnormal ABR but normal results of DPOAE were enrolled in the study group. The mean patient age was one year and one-month-old, with a range of 8 days to 7 years. The cases with abnormal conductive function were excluded. The cases with severely abnormal ABR and normal cochlear functions as measured by DPOAE and without abnormal conductive function were selected as the cochlear lesion group. Some same age healthy children without hearing loss were subjected as normal control group. The latency and amplitude of waves I, III and V, the inter peak latency I-III was compared among the three group. RESULTS: (1) Fifty-one cases (59.3%) had a history of hypercholesterolemia during neonatal period, but 40 cases (46.51%) had a severe hypercholesterolemia and 11 cases (12.79%) had mild or moderate hypercholesterolemia. Clinical features common among the population included a history of dyskinesia [n = 40 (46.51%)], hearing and language disorder [n = 10 (11. 63%)]. Thirty-two cases (37.2%) were accompanied by cerebral palsy . (2) Among the 165 ears, absent ABRs to click stimuli presented at 103 dB was in 103 ears, only wave I was developed in 27 ears and only wave V was developed in 19 ears,wave I and III in 13 ears and differentiated wave I and V in 3 ears. (3) When compared to control group, the latency of wave I was prolonged and amplitude of wave I was lower in cases with only wave I developed (t = -6.75 and 2.58, P < 0.05). For for cases with only wave I and III differentiated, the latency and amplitude of wave I was the same but the latency of wave III was prolonged and amplitude of wave III was lower while interpeak latency I-III was prolonged. CONCLUSIONS: Auditory neuropathy which was characterized by severely abnormal ABR was the most common type of retrocochlear auditory nerve impairment. It was mainly due to a disorder of VIII nerve. The pathologies that affect higher levels of the auditory pathway, from the brainstem to the auditory cortex, might be the main sites of lesion in cases with only wave I developed. Superior olivary nucleus where wave III was generated and higher levels of the auditory pathway might be the main sites of lesion in cases with wave I and III differentiated. The low-amplitude wave V was not characteristics of auditory neuropathy. Cerebral cortex, brain stem auditory nucleus and VIII nerve might be damaged successively in cases with retrocochlear auditory nerve impairment induced by hypercholesterolemia.

[Hearing evaluation of infants failed in hearing screening].

OBJECTIVE: To analyze the confusing factors and clinical and audiological characteristics in infants failed in hearing screening. METHODS: Between August 2004 and January 2006, 166 infants (315 ears) with detailed birth record and hearing screening record were reviewed in the study. The age of this series ranged from 2 to 6 months. They were born in maternal and child health hospitals (MCH) in Guangzhou city and surrounding areas, and had hearing screened by otoacoustic emissions (OAE). However, they failed in the first and second hearing screening. The birth history, high-risk factors of hearing-impaired during newborn period and pregnancy history of subjects were fully detailed. Subjects were classified according to the age: 2 to 3 months old infants were considered as group 1, while 4 to 6 months old infants were considered as group 2. Auditory brainstem response (ABR), distortion product otoacoustic emissions (DPOAE) and acoustic immittance measurement were examined. Subjects with abnormal hearing-evaluation were retested during the following one to three months (before 6-month-old). The ABR results, DPOAE results and tympanic cavity pressure and static compliance value were compared between the two tests and then diagnosis was made. RESULTS: (1) Among the 166 cases, 34 (20.5%) cases were once suffered from hypercholesterolemia of newborn, and 10 cases (6.0%) had asphyxia and hypoxia history. (2) The proportion of presenting type B tympanogram in group 2 was higher than that of group 1 (chi2 = 26.22, P < 0.01). (3) The proportion of normal ABR in group 2 (37.2%) was significantly higher than that of in group 1 (23.4%, chi2 = 0.527, P < 0.05). Fifty-six percent of infants accepted twice ABR test had improving ABR results during the second test. (4) The proportion of normal DOPAE in group 2 (39.7%) was slightly lower than that of in group 1 (42.2%, chi2 = 0.14, P > 0.05). Among the infants who accepted twice DPOAE test, 32.0% had improving results in the second test. (5) Four cases (4 ears ) were diagnosed as auditory neuropathy. CONCLUSIONS: Middle ear function and development of auditory system in infants may be confusing factors in hearing screening. The results of hearing screening should be interpreted appropriately.