CIB2 mediates acquired gefitinib resistance by inducing ZEB1 expression and epithelial-mesenchymal transition.

EGFR-TKIs have been used as frontline treatment in patients with advanced non-small cell lung cancer (NSCLC) suffering from the EGFR mutation. Gefitinib, the first-generation EGFR-TKI, has greatly improved survival rates in lung cancer patients, whereas acquired gefitinib resistance is still a critical issue that needs to be overcome. In our research, high expression levels of CIB2 were found in gefitinib-resistant lung cancer cells. CIB2 knockout rendered gefitinib-resistant cells more sensitive to gefitinib, and overexpression of CIB2 in parental cells was sufficient to induce more resistance to gefitinib. Inhibition of CIB2 in gefitinib-resistant lung cancer cells significantly induced cell apoptosis. To clarify the major molecular mechanism by which CIB2 increases gefitinib resistance, we demonstrated that raised CIB2 in lung cancer cells promoted epithelial-to-mesenchymal transition (EMT) through upregulation of ZEB1. Moreover, FOSL1 transcriptionally regulated CIB2 expression. Finally, CIB2 rendered tumors resistant to gefitinib treatment in vivo. Our results explored a new mechanism: upregulated CIB2 promoted EMT through ZEB1 to regulate gefitinib resistance, which could be a candidate therapeutic target for overcoming acquired resistance to EGFR-TKIs in NSCLC patients.

Potential Use of ChatGPT for the Treatment of Infectious Diseases in Vulnerable Populations.

BACKGROUND: ChatGPT could be a useful tool in the infectious disease field. However, the application of ChatGPT for the treatment of infectious diseases in vulnerable population has not been determined. METHODS: We designed questions about antibiotic use, including the choice of antibiotics, dose, and treatment duration for prevalent infectious disease in vulnerable populations. Each query was posed to ChatGPT-4, and the answers were independently evaluated by two authors. When there were significant differences in the final scores between the two authors, they discussed the case and answers to obtain results. RESULTS: Our analysis revealed that 38.1% of responses were comprehensive and correct, with 11.9% containing errors for medication use for patients during pregnancy. For the antibiotic allergy-related questions, 36.1% of responses were comprehensive and correct, and 18.1% contained errors. For older adults, 27.5% of responses were comprehensive and correct, while 25% contained errors. The error rate in patients with kidney disease was 79.2%. For children, 43.8% of answers contained errors. CONCLUSION: ChatGPT produced high rates of inaccurate information for treating infectious diseases in special population. Thus, recommendations generated by ChatGPT should be used with caution and checked by healthcare professionals to ensure accuracy and comprehensiveness prior to use.

HDAC1 and FOXK1 mediate EGFR-TKI resistance of non-small cell lung cancer through miR-33a silencing.

BACKGROUND: The development of acquired EGFR-TKI treatment resistance is still a major clinical challenge in the treatment of non-small cell lung cancer (NSCLC). This study aimed to investigate the role of HDAC1/FOXK1/miR-33a signaling in EGFR-TKI resistance. METHODS: The expression levels of miR-33a, HDAC1, and FOXK1 were examined using quantitative polymerase chain reaction (PCR) and bioinformatics analysis. Cell proliferation, migration, and apoptosis were explored by cell number assay, Transwell, and flow cytometry assays, respectively. After overexpression or knockdown of HDAC1, miR-33a expression in the cells, cell functions were tested. Immunoprecipitation and correlation analyses were used to evaluate the interaction between HDAC1 and FOXK1 protein. The tumor-suppressive role of miR-33a was investigated by animal experiments. RESULTS: The suppression of miR-33a increased TKI resistance by affecting cell proliferation, migration, and apoptosis in gefitinib-resistant cells. HDAC1 is the key upstream molecule that inhibits miR-33 expression. HDAC1 upregulation increased gefitinib resistance by its binding to FOXK1 in cells to silence miR-33a expression. MiR-33a overexpression exerts tumor-suppressive effects by negatively regulating ABCB7 and p70S6K1 expression. Moreover, overexpression of miR-33a inhibited tumor growth in a xenograft nude mouse model. CONCLUSIONS: HDAC1/FOXK1 upregulation and miR-33a silencing are new mechanisms of EGFR-TKI resistance in NSCLC.

HK2 and LDHA upregulation mediate hexavalent chromium-induced carcinogenesis, cancer development and prognosis through miR-218 inhibition.

Hexavalent chromium [Cr(VI)] is one of the most common environmental contaminants due to its tremendous industrial applications, but its effects and mechanism remain to be investigated. Our previous studies showed that Cr(VI) exposure caused malignant transformation and tumorigenesis. This study showed that glycolytic proteins HK2 and LDHA levels were statistically significant changed in blood samples of Cr(VI)-exposed workers and in Cr-T cells compared to the control subjects and parental cells. HK2 and LDHA knockdown inhibited cell proliferation and angiogenesis, and higher HK2 and LDHA expression levels are associated with advanced stages and poor prognosis of lung cancer. We found that miR-218 levels were significantly decreased and miR-218 directly targeted HK2 and LDHA for inhibiting their expression. Overexpression of miR-218 inhibited glucose consumption and lactate production in Cr-T cells. Further study found that miR-218 inhibited tumor growth and angiogenesis by decreasing HK2 and LDHA expression in vivo. MiR-218 levels were negatively correlated with HK2 and LDHA expression levels and cancer development in human lung and other cancers. These results demonstrated that miR-218/HK2/LDHA pathway is vital for regulating Cr(VI)-induced carcinogenesis and human cancer development.

Self acceleration from spectral geometry in dissipative quantum-walk dynamics.

The dynamic behavior of a physical system often originates from its spectral properties. In open systems, where the effective non-Hermitian description enables a wealth of spectral structures in the complex plane, the concomitant dynamics are significantly enriched, whereas the identification and comprehension of the underlying connections are challenging. Here we experimentally demonstrate the correspondence between the transient self-acceleration of local excitations and the non-Hermitian spectral topology using lossy photonic quantum walks. Focusing first on one-dimensional quantum walks, we show that the measured short-time acceleration of the wave function is proportional to the area enclosed by the eigenspectrum. We then reveal a similar correspondence in two-dimension quantum walks, where the self-acceleration is proportional to the volume enclosed by the eigenspectrum in the complex parameter space. In both dimensions, the transient self-acceleration crosses over to a long-time behavior dominated by a constant flow at the drift velocity. Our results unveil the universal correspondence between spectral topology and transient dynamics, and offer a sensitive probe for phenomena in non-Hermitian systems that originate from spectral geometry.

Experimental Observation of the Yang-Lee Quantum Criticality in Open Quantum Systems.

The Yang-Lee edge singularity was originally studied from the standpoint of mathematical foundations of phase transitions. However, direct observation of anomalous scaling with the negative scaling dimension has remained elusive due to an imaginary magnetic field required for the nonunitary criticality. We experimentally implement an imaginary magnetic field with an open quantum system of heralded single photons, directly measure the partition function, and demonstrate the Yang-Lee edge singularity via the quantum-classical correspondence. We also demonstrate unconventional scaling laws for finite-temperature quantum dynamics.

Performance of the 2019 ACR/EULAR Classification Criteria for IgG4-Related Disease in a Large Chinese Cohort.

OBJECTIVE: The purpose of this research was to ascertain the effectiveness of the newly established criteria for classifying IgG4-related disease (IgG4-RD), as applied to a large Chinese cohort in real-world clinical settings. METHODS: Patient data were procured from the digital health records of 4 prominent academic hospitals. The criterion standard for identifying IgG4-RD patients was from a seasoned rheumatologist. The control group consisted of individuals with other ailments such as cancer, other forms of pancreatitis, infectious diseases, and illnesses that mimic IgG4-RD. RESULTS: A total of 605 IgG4-RD patients and 760 mimickers were available for analysis. The 2019 EULAR/ACR criteria have a sensitivity of 69.1% and a specificity of 90.9% in this large Chinese cohort. IgG4-RD had a greater proportion of males (55.89% vs 36.25%, p < 0.001), an older average age at diagnosis (54.91 ± 13.44 vs 48.91 ± 15.71, p < 0.001), more pancreatic (29.59% vs 6.12%, p < 0.001) and salivary gland (63.30% vs 27.50%, p < 0.001) involvement, and a larger number of organ involvement (3.431 ± 2.054 vs 2.062 ± 1.748, p < 0.001) compared with mimickers. CONCLUSIONS: The 2019 EULAR/ACR criteria are effective in classifying IgG4-RD in Chinese patients, demonstrating high specificity and moderate sensitivity.

PxRdl2 dsRNA increased the insecticidal activities of GABAR-targeting compounds against Plutella xylostella.

The utilization of RNA interference (RNAi) for pest management has garnered global interest. The bioassay results suggested the knockout of the PxRdl2 gene significantly increased the insecticidal activities of the γ-aminobutyric acid receptor (GABAR)-targeting compounds (fipronil, two pyrazoloquinazolines, and two isoxazolines), thereby presenting a viable target gene for RNAi-mediated pest control. Consequently, we suggest enhancing the insecticidal activities of GABAR-targeting compounds by knockdown the transcript level of PxRdl2. Furthermore, PxRdl2 dsRNA was expressed in HT115 Escherichia coli to reduce costs and protect dsRNA against degradation. In comparison to in vitro synthesized dsRNA, the recombinant bacteria (ds-B) exhibited superior interference efficiency and greater stability when exposed to UV irradiation. Collectively, our results provide a strategy for insecticide spray that combines synergistically with insecticidal activities by suppressing PxRdl2 using ds-B and may be beneficial for reducing the usage of insecticide and slowing pest resistance.

Experimental simulation of symmetry-protected higher-order exceptional points with single photons.

Exceptional points (EPs) of non-Hermitian (NH) systems have recently attracted increasing attention due to their rich phenomenology and intriguing applications. Compared to the predominantly studied second-order EPs, higher-order EPs have been assumed to play a much less prominent role because they generically require the tuning of more parameters. Here, we experimentally simulate two-dimensional topological NH band structures using single-photon interferometry, and observe topologically stable third-order EPs obtained by tuning only two real parameters in the presence of symmetry. In particular, we explore how different symmetries stabilize qualitatively different third-order EPs: the parity-time symmetry leads to a generic cube-root dispersion, while a generalized chiral symmetry implies a square-root dispersion coexisting with a flat band. Additionally, we simulate fourfold degeneracies, composed of the non-defective twofold degeneracies and second-order EPs. Our work reveals the abundant and conceptually richer higher-order EPs protected by symmetries and offers a versatile platform for further research on topological NH systems.

Observation of dark edge states in parity-time-symmetric quantum dynamics.

Topological edge states arise in non-Hermitian parity-time ([Formula: see text])-symmetric systems, and manifest themselves as bright or dark edge states, depending on the imaginary components of their eigenenergies. As the spatial probabilities of dark edge states are suppressed during the non-unitary dynamics, it is a challenge to observe them experimentally. Here we report the experimental detection of dark edge states in photonic quantum walks with spontaneously broken [Formula: see text] symmetry, thus providing a complete description of the topological phenomena therein. We experimentally confirm that the global Berry phase in [Formula: see text]-symmetric quantum-walk dynamics unambiguously defines topological invariants of the system in both the [Formula: see text]-symmetry-unbroken and -broken regimes. Our results establish a unified framework for characterizing topology in [Formula: see text]-symmetric quantum-walk dynamics, and provide a useful method to observe topological phenomena in [Formula: see text]-symmetric non-Hermitian systems in general.

Corrigendum to 'The Fudan tinnitus relieving system application for tinnitus management' [Internet Interv. 29 (2022): 100564].

[This corrects the article DOI: 10.1016/j.invent.2022.100564.].

MKRN2 knockout causes male infertility through decreasing STAT1, SIX4, and TNC expression.

Makorin-2 (Mkrn2) is an evolutionarily conserved gene whose biological functions are not fully known. Although recent studies have shed insights on the potential causes of male infertility, its underlining mechanisms still remain to be elucidated. We developed a Mrkn2 knockout mice model to study this gene and found that deletion of Mkrn2 in mice led to male infertility. Interestingly, the expression level of signal transducer and activator of the transcription (STAT)1 was significantly decreased in MKRN2 knockout testis and MEF cells. Co-IP assay showed an interaction between MKRN2 and STAT1. Moreover, our results further indicated that MKRN2 regulated the expression level of SIX4 and tenascin C (TNC) via the EBF transcription factor 2 (EBF2) in mice. The results of our study will provide insights into a new mechanism of male infertility.

A novel V263I mutation in the glutamate-gated chloride channel of Plutella xylostella (L.) confers a high level of resistance to abamectin.

The frequent and extensive use of insecticides leads to the evolution of insecticide resistance, which has become one of the constraints on global agricultural production. Avermectins are microbial-derived insecticides that target a wide number of insect pests, including the diamondback moth Plutella xylostella, an important global pest of brassicaceous vegetables. However, field populations of P. xylostella have evolved serious resistance to avermectins, including abamectin, thereby threatening the efficiency of these insecticides. In this study, a novel valine to isoleucine mutation (V263I) was identified in the glutamate-gated chloride channel (GluCl) of field P. xylostella populations, which showed different levels of resistance to abamectin. Electrophysiological analysis revealed that the V263I mutation significantly reduced the sensitivity of PxGluCl to abamectin by 6.9-fold. Genome-modified Drosophila melanogaster carrying the V263I mutation exhibited 27.1-fold resistance to abamectin. Then, a knockin strain (V263I-KI) of P. xylostella expressing the homozygous V263I mutation was successfully constructed using the CRISPR/Cas9. The V263I-KI had high resistance to abamectin (106.3-fold), but significantly reduced fecundity. In this study, the function of V263I mutation in PxGluCl was verified for the first time. These findings provide a more comprehensive understanding of abamectin resistance mechanisms and lay the foundation for providing a new molecular detection method for abamectin resistance monitoring.

Use of SAMe-TT2R2 in a racially diverse anticoagulation clinic: prediction of optimal anticoagulation.

The SAMe-TT2R2 score predicts optimal long-term oral Vitamin K Antagonist (VKA) anticoagulation for homogenous Caucasian and homogenous Asian populations for non-valvular atrial fibrillation but at different score thresholds. The score that predicts optimal VKA anticoagulation in significantly diverse populations for multiple indications for systemic anticoagulation has not been reported. We determined whether optimal VKA anticoagulation is predicted by SAMe-TT2R2 score in a diverse inner-city population for non-valvular atrial fibrillation (NVAF), unprovoked venous and pulmonary thromboembolic disease (VTE), mechanical prosthetic heart valves and all other indications. All patients on long term VKA's that attended an inner-city anticoagulation clinic between February 2016 and October 2017 were included in this study. Eligible patients were grouped according to oral anticoagulation indication: (1) NVAF, (2) VTE, (3) prosthetic valves and (4) other indications. Each patient's SAMe-TT2R2 score and percent time of INR in the therapeutic range (TTR) was calculated with optimal international normalized ratio (INR) control defined as TTR ≥ 65%. The correlation between SAMe-TT2R2 score and TTR was determined by logistic regression for each oral anticoagulant indication. Receiver operating characteristic curves were then used to identify the best cutoff for prediction of ≥ 65% TTR. Of 316 patients meeting study criteria, 54% were non-Caucasian and there was a significant negative correlation between the SAMe-TT2R2 score and TTR (coefficient - 0.35, P < 0.0001) for all patients. A SAMe-TT2R2 score < 4 was identified as the best threshold for predicting optimal TTR (Youden's J-statistics = 0.238) with accuracy and positive likelihood ratio of 63.4% and 1.73, respectively. The SAMe-TT2R2 score predicts optimal VKA anticoagulation for systemic anticoagulation for multiple indications in a diverse urban population at a higher score than the original report for non-valvular atrial fibrillation of a cohort where < 10% non-Caucasians.

Optimizing phosphate fertilizer input to reduce phosphorus loss in rice-oilseed rape rotation.

Identifying the major sources and critical periods of P loss from agricultural fields provides important guidance for reducing P loss. A rice-oilseed rape rotation with no P fertilization (NP, control), medium P fertilization (MP, 90 kg P2O5 ha-1 season-1), and high P fertilization (HP, 180 kg P2O5 ha-1 season-1) was conducted from 2019 to 2021 in the middle Yangtze River Basin. Runoff and leaching P losses were measured simultaneously using runoff event monitoring and a percolation device. Applying P fertilizer increased the P concentration in the field ponding water and percolation water of the rice-oilseed rape rotation. During the rice growing season, total P (TP), dissolved P (DP), and particulate P (PP) concentrations in the field ponding water and percolation water peaked 1 day after P was applied, and then decreased rapidly. After 10 days of fertilization, P concentration in the field ponding water of the MP treatment decreased to a minimum and stabilized, while the HP treatment extended this period to 20 days. The highest P concentration in percolation water was observed at the first sampling during the oilseed rape season, and then it continued to decrease. Inputting P fertilizer increased P loss by 55.0-109.9% compared to the NP treatment, with annual P losses of 0.89-1.10 kg P ha-1, of which runoff loss accounted for 61.7-62.9%. Fertilization and precipitation resulted in varied P loss within and between seasons. Runoff from heavy precipitation during the rice season was the main source of P loss, while PP accounted for 54.7-77.6% of runoff P loss. The strong utilization of soil P by rice resulted in a lower demand for exogenous P fertilizer than oilseed rape. Excessive P input increased the soil P surplus and vertical migration. Therefore, reducing rice season P fertilizer inputs to achieve annual P balance in rice-oilseed rape rotation can effectively reduce soil P surplus and loss while ensuring crop P demand, and the initial 10 d after fertilization in the rice season was a critical period for reducing P runoff loss.

The Use of Hydrocortisone, Ascorbic Acid and Thiamine in Patients with Sepsis and Septic Shock - A Systematic Review.

Background: Sepsis and septic shock are associated with enormous mortality and health care burden. Since the study of Marik et al suggested mortality benefit, there has been great interest in evaluating the role of hydrocortisone, ascorbic acid and thiamine (HAT therapy) in sepsis and septic shock. Purpose: The objective of this article is to review current literature of using HAT therapy in sepsis and septic shock, and discuss the findings in hospital mortality, change in 72 hr SOFA score, other outcomes, and the study limitations. Research Design: Three databases (PubMed, Embase, and Cochrane) were screened using predefined search terms ascorbic acid, vitamin C, thiamine, vitamin B1, hydrocortisone, sepsis, septic shock. Study Sample: Data extracted from eligible studies include authors, publication year, sample size, study design, intervention, outcome measures and study results. Each study was reviewed critically. Results: Among 11 studies included in this literature review, 3 studies reported HAT therapy was associated with mortality benefit, 1 reported hospital mortality was significantly higher in HAT group and the rest of studies didn't reach statistical significance in mortality analysis. Significant improvement of secondary outcomes, although not consistently, were reported. Conclusions: In conclusion, HAT therapy has demonstrated a good safety profile and potential benefits in management of sepsis and septic shock. Further research is required to confirm these findings.

Application of auditory mismatch negativity in tinnitus patients based on high-resolution electroencephalogram signals.

Objective: The purpose of this study was to investigate the significance of mismatch negativity (MMN) by comparing high-resolution electroencephalogram signals from tinnitus patients and healthy controls. Methods: The study included eight subjects with chronic subjective idiopathic tinnitus and seven healthy controls. Participants with clinical speech (512-2,000 Hz) hearing thresholds less than 25 dB HL and with negative Hospital Anxiety and Depression Scale scores were included in the study. The E-Prime 2.0 software and a 256-electrode EGI Net Station system were used to evoke and record the MMN signal, and the amplitude and latency parameters of the MMN responses were compared between the two groups. Results: From 150 ms, there was a significant difference between the amplitude of standard stimulation and deviation stimulation, and the event-related potential amplitude under deviation stimulation in the tinnitus patient group was significantly different from that in the healthy group. The MMN amplitude of the FCz electrode was statistically significantly lower in the tinnitus patients compared to healthy controls. Conclusion: MMN has application value in the evaluation of abnormal electrical activity in the auditory pathway, and electroencephalograms are feasible for follow-up monitoring after acoustic therapy.

Loss of Mst1/2 activity promotes non-mitotic hair cell generation in the neonatal organ of Corti.

Mammalian sensory hair cells (HCs) have limited capacity for regeneration, which leads to permanent hearing loss after HC death. Here, we used in vitro RNA-sequencing to show that the Hippo signaling pathway is involved in HC damage and self-repair processes. Turning off Hippo signaling through Mst1/2 inhibition or Yap overexpression induces YAP nuclear accumulation, especially in supporting cells, which induces supernumerary HC production and HC regeneration after injury. Mechanistically, these effects of Hippo signaling work synergistically with the Notch pathway. Importantly, the supernumerary HCs not only express HC markers, but also have cilia structures that are able to form neural connections to auditory regions in vivo. Taken together, regulating Hippo suggests new strategies for promoting cochlear supporting cell proliferation, HC regeneration, and reconnection with neurons in mammals.

The Fudan Tinnitus Relieving System (FTRS): The initial results of a smartphone application for tinnitus management and treatment.

Objective: Tinnitus is highly prevalent in the population, but there are currently few effective therapeutic interventions. Mobile applications (apps) might be helpful in tinnitus diagnosis and treatment by offering sound or music tools as well as questionnaires. We assessed the efficacy of a free, publicly available smartphone app (Fudan Tinnitus Relieving System, FTRS) for self-management of tinnitus and related symptoms. Methods: Among a total of 3564 participants recruited primarily online, 2744 patients had complete information at baseline and were an average of 37 years old and were 59.84 % male. Web-administered self-report measures THI, HADS, AIS, and other multi-dimensional scales were conducted at baseline and at 1 month and 2 months following treatment. Data from 54 participants who completed continuous follow-up were used for the final efficacy analysis and longitudinal analysis. Results: Following the intent-to-treat principle, t-tests revealed that the distribution of patients and the tinnitus features of patients of different genders were heterogeneous. One-way ANOVA showed that after using the FTRS app, THI scores showed a decreasing trend (p < 0.001). Conclusion: FTRS use resulted in significantly greater improvements in tinnitus and other outcomes relative to their baseline condition before treatment. Given the ubiquity of smartphones, FTRS may provide a wide-reaching and convenient public health intervention for individuals with tinnitus symptoms.

Topological Phase Transitions and Mobility Edges in Non-Hermitian Quasicrystals.

Non-Hermiticity significantly enriches the properties of topological models, leading to exotic features such as the non-Hermitian skin effects and non-Bloch bulk-boundary correspondence that have no counterparts in Hermitian settings. Its impact is particularly illustrating in non-Hermitian quasicrystals where the interplay between non-Hermiticity and quasiperiodicity results in the concurrence of the delocalization-localization transition, the parity-time (PT)-symmetry breaking, and the onset of the non-Hermitian skin effects. Here, we experimentally simulate non-Hermitian quasicrystals using photonic quantum walks. Using dynamic observables, we demonstrate that the system can transit from a delocalized, PT-symmetry broken phase that features non-Hermitian skin effects, to a localized, PT-symmetry unbroken phase with no non-Hermitian skin effects. The measured critical point is consistent with the theoretical prediction through a spectral winding number, confirming the topological origin of the phase transition. More interestingly, we also provide the first experimental evidence for mobility edges which are induced by non-Hermiticity. Our Letter opens the avenue of investigating the interplay of non-Hermiticity, quasiperiodicity, and spectral topology in open quantum systems.