Chemical and chemoenzymatic syntheses of sialyl Lewisa tetrasaccharide antigen.

Sialyl Lewisa (sLea), also known as cancer antigen 19-9, is a tumor-associated carbohydrate antigen. In this article, chemical and chemoenzymatic syntheses of a tetrasaccharide glycan 1 structurally derived from sLea are reported. Challenges involved in the chemical synthesis include the highly stereoselective construction of 1,2-cis-α-L-fucoside and α-D-sialoside, as well as the assembly of the 3,4-disubstituted N-acetylglucosamine subunit. Perbenzylated thiofucoside and N-acetyl-5-N,4-O-oxazolidinone protected sialic acid thioglycoside were employed as glycosyl donors, respectively, for the efficient preparation of the desired α-fucoside and α-sialoside. The 3,4-branched glucosamine backbone was established through a 3-O and then 4-O glycosylation sequence in which the 3-hydroxyl group of the glucosamine moiety was glycosylated first and then the 4-hydroxyl. A facile chemoenzymatic approach was also exploited to synthesize the target molecule. The chemically obtained free disaccharide 30 was sequentially sialylated and fucosylated in an enzyme-catalyzed regio- and stereospecific manner to form 1 in high yields. The linker appended 1 can be covalently attached to a carrier protein for further immunological studies.

microRNA-15a-5p suppresses hypoxia-induced tumor growth and chemoresistance in bladder cancer by binding to eIF5A2.

In various malignant tumors (including bladder cancer) poor prognosis is associated with hypoxia and therapeutic resistance. Evidence indicates that in bladder cancer, microRNAs (miRNAs) have vital functions in acquired drug resistance. However, the involvement of miRNAs in hypoxia-mediated bladder cancer doxorubicin (Dox) resistance is unknown. Herein, we showed that hypoxia and Dox treatment downregulated miR-15a-5p expression. Using UM-UC-3 and J82 bladder cancer cell lines and in vivo mouse models of bladder cancer, we confirmed that miR-15a-5p arrests tumor cell growth and Dox resistance in vitro and in vivo. Furthermore, we determined the interaction between miR-15a-5p and eukaryotic translation initiation factor 5A-2 (eIF5A2) using dual luciferase reporters and quantitative real-time reverse transcription polymerase chain reaction assays. We also showed that a miR-15a-5p agomir repressed EIF5A2 expression in bladder cancer cells, thereby inhibiting the epithelial-mesenchymal transition (EMT) induced by Dox or hypoxia. Moreover, ectopic expression of miR-15a-5p abrogated eIF5A2-mediated Dox resistance in bladder cancer cells. Collectively, these data indicated that hypoxia promotes tumor growth and chemoresistance through the HIF-1α/miR-15a-5p/eIFTA2/EMT pathway. This new finding not only has implications for improving our understanding of the Dox resistance process during bladder cancer progression but also indicates that the miR-15a-5p agomir is a promising tool to prevent Dox resistance in patients with bladder cancer.

Role of early hearing aid experience in speech recognition in patients with bilateral congenital microtia following Bonebridge implantation: a retrospective cohort study.

PURPOSE: To identify audiological and demographic variables that predict speech recognition abilities in patients with bilateral microtia who underwent Bonebridge (BB) implantation. METHODS: Fifty patients with bilateral microtia and bilateral conductive hearing loss (CHL) who underwent BB implantation were included. Demographic data, preoperative hearing aid use experience, and audiological outcomes (including pure-tone hearing threshold, sound field hearing threshold [SFHT], and speech recognition ability) for each participant were obtained. The Chinese-Mandarin Speech Test Materials were used to test speech recognition ability. The word recognition score (WRS) of disyllabic words at 65 dB SPL signals was measured before and after BB implantation in quiet and noisy conditions. RESULTS: The mean preoperative WRS under quiet and noisy conditions was 10.44 ± 12.73% and 5.90 ± 8.76%, which was significantly improved to 86.38 ± 9.03% and 80.70 ± 11.34%, respectively, following BB fitting. Multiple linear regression analysis revealed that lower preoperative SFHT suggested higher preoperative WRS under both quiet and noisy conditions. Higher age at implantation predicted higher preoperative WRS under quiet conditions. Furthermore, patients with more preoperative hearing aid experience and lower postoperative SFHT were more likely to have higher postoperative WRS under both quiet and noisy testing conditions. CONCLUSIONS: This study represents the first attempt to identify predictors of preoperative and postoperative speech recognition abilities in patients with bilateral microtia with BB implantation. These findings emphasize that early hearing intervention before implantation surgery, combined with appropriate postoperative fitting, contributes to optimal benefits in terms of postoperative speech recognition ability.

A new active bone-conduction implant: surgical experiences and audiological outcomes in patients with bilateral congenital microtia.

PURPOSE: First-generation bone bridges (BBs) have demonstrated favorable safety and audiological benefits in patients with conductive hearing loss. However, studies on the effects of second-generation BBs are limited, especially among children. In this study, we aimed to explore the surgical and audiological effects of second-generation BBs in patients with bilateral congenital microtia. METHODS: This single-center prospective study included nine Mandarin-speaking patients with bilateral microtia. All the patients underwent BCI Generation 602 (BCI602; MED-EL, Innsbruck, Austria) implant surgery between September 2021 and June 2023. Audiological and sound localization tests were performed under unaided and BB-aided conditions. RESULTS: The transmastoid and retrosigmoid sinus approaches were implemented in three and six patients, respectively. No patient underwent preoperative planning, lifts were unnecessary, and no sigmoid sinus or dural compression occurred. The mean function gain at 0.5-4.0 kHz was 28.06 ± 4.55-dB HL. The word recognition scores improved significantly in quiet under the BB aided condition. Signal-to-noise ratio reduction by 10.56 ± 2.30 dB improved the speech reception threshold in noise. Patients fitted with a unilateral BB demonstrated inferior sound source localization after the initial activation. CONCLUSIONS: Second-generation BBs are safe and effective for patients with bilateral congenital microtia and may be suitable for children with mastoid hypoplasia without preoperative three-dimensional reconstruction.

Track Irregularity Identification Method of High-Speed Railway Based on CNN-Bi-LSTM.

Track smoothness has become an important factor in the safe operation of high-speed trains. In order to ensure the safety of high-speed operations, studies on track smoothness detection methods are constantly improving. This paper presents a track irregularity identification method based on CNN-Bi-LSTM and predicts track irregularity through car body acceleration detection, which is easy to collect and can be obtained by passenger trains, so the model proposed in this paper provides an idea for the development of track irregularity identification method based on conventional vehicles. The first step is construction of the data set required for model training. The model input is the car body acceleration detection sequence, and the output is the irregularity sequence of the same length. The fluctuation trend of the irregularity data is extracted by the HP filtering (Hodrick Prescott Filter) algorithm as the prediction target. The second is a prediction model based on the CNN-Bi-LSTM network, extracting features from the car body acceleration data and realizing the point-by-point prediction of irregularities. Meanwhile, this paper proposes an exponential weighted mean square error with priority inner fitting (EIF-MSE) as the loss function, improving the accuracy of big value data prediction, and reducing the risk of false alarms. In conclusion, the model is verified based on the simulation data and the real data measured by the high-speed railway comprehensive inspection train.

Quantum Oppenheimer-Snyder and Swiss Cheese Models.

By considering the quantum Oppenheimer-Snyder model in loop quantum cosmology, a new quantum black hole model whose metric tensor is a suitably deformed Schwarzschild one is derived. The quantum effects imply a lower bound on the mass of the black hole produced by the collapsing dust ball. For the case of larger masses where the event horizon does form, the maximal extension of the spacetime and its properties are investigated. By discussing the opposite scenario to the quantum Oppenheimer-Snyder, a quantum Swiss Cheese model is obtained with a bubble surrounded by the quantum universe. This model is analogous to black hole cosmology or fecund universes where the big bang is related to a white hole. Thus our models open a new window to cosmological phenomenology.

Neoadjuvant chemoradiotherapy plus tislelizumab followed by surgery for esophageal carcinoma (CRISEC study): the protocol of a prospective, single-arm, phase II trial.

BACKGROUND: The failure rate after neoadjuvant chemoradiotherapy followed by surgery is approximately 34.6%-48% for resectable esophageal carcinoma. Pathologic complete response after neoadjuvant chemoradiotherapy is an important factor in predicting lower recurrence and better survival. Whether the sequential addition of immunotherapy to neoadjuvant chemoradiotherapy will be beneficial to improving the pathologic complete response rate is unknown. METHODS: Patients with pathologically confirmed thoracic esophageal squamous cell carcinoma and at clinical T1-2N1-3M0 or T3-4aN0-3M0 (stage II-IVA) according to the eighth edition of American Joint Committee on Cancer staging will be allocated to receive neoadjuvant radiotherapy (41.4 Gy with 23 fractions to planning target volume) with concurrent chemotherapy (albumin-bound paclitaxel, 100 mg/m2, once weekly for five weeks; carboplatin, area under the curve of 2 mg/mL/min, once weekly for five weeks) plus tislelizumab monotherapy sequentially (200 mg every three weeks for three cycles, beginning from the first to the 14th day after the end of radiotherapy). Then, subtotal esophagectomy with two-field lymphadenectomy, including the whole mediastinum and abdomen, will be performed. The primary endpoint for this study is the pathologic complete response rate after neoadjuvant chemoradiotherapy plus tislelizumab. DISCUSSION: The optimal timing of the combination of immunotherapy and neoadjuvant chemoradiotherapy in esophageal carcinoma is not determined. The results of this phase II trial will be helpful to clarify the safety and efficacy of the sequential addition of tislelizumab after neoadjuvant chemoradiotherapy for locally advanced resectable esophageal carcinoma. TRIAL REGISTRATION: This study was approved on January 26, 2021 and retrospectively registered with ClinicalTrials.gov ( NCT04776590 ) on March 1, 2021.

Optimal Choice for Improving the Hearing in Children with Unilateral Microtia and Atresia: Softband or Adhesive Adapter?

INTRODUCTION: A nonsurgical bone conduction hearing aid (BCHA) is a well-established treatment for children with congenital unilateral microtia and atresia (UMA). To date, limited studies have evaluated the audiological characteristics of the different wearing modes in the same nonsurgical BCHA. METHODS: Eighteen patients with UMA aged 5-24 years were included. Warble tones at frequencies of 0.5, 1, 2, and 4 kHz were presented to determine functional hearing gain (FHG) of hearing thresholds (in dB HL) in the sound field. The speech perception abilities were assessed by the speech discrimination score (SDS, in %) of monosyllables, disyllables, and sentences in quiet and noise using the Chinese Mandarin speech test materials. Hearing outcomes were evaluated with the ADHEAR™ worn on a softband and with an adhesive adapter. A correlational analysis was conducted to analyze the correlations between variables (e.g., age, height, weight, body mass index [BMI], bone conduction pure-tone threshold, and air conduction pure-tone threshold) and the differences in the two wearing modes. RESULTS: The mean FHG (standard deviation, SD) at 0.5-4 kHz was 20.63 (3.94) dB HL with the adhesive adapter and 26.39 (3.15) dB HL with the softband. When aided with the BCHA, significant improvements in SDS were revealed in all Mandarin speech test material lists either in quiet or noise for both wearing modes. Compared with the adapter mode, the softband provided higher aided SDS values. Correctional analyses revealed that higher BMI values were positively associated with larger delta outcomes between the two coupling methods of the softband and adhesive adapter in patients with UMA. Furthermore, a larger delta average FHG of 0.5-4 kHz was consistently associated with larger delta monosyllabic SDS in quiet, disyllabic SDS in quiet, and disyllabic SDS in noise. DISCUSSION: To the best of our knowledge, this is the first study to compare the hearing benefits of coupling methods using novel adhesive adapters and conventional softbands with the same audio processor (ADHEAR™). Under uniform internal settings, softband integration provided more hearing benefits than adhesive adapter integration, and the differences were more obvious in patients with higher BMI values. Besides, a brief measurement of FHG can be utilized to predict individualized speech perception levels.

MicroRNA-133a-3p inhibits lung adenocarcinoma development and cisplatin resistance through targeting GINS4.

GINS subunit complex 4 (GINS4) is fundamental to DNA replication and G1/S phase transition of the cell cycle in eukaryotes. Further, recent studies implied that GINS4 can mediate the progression of several tumors, but its mechanism in lung adenocarcinoma (LUAD) is not clarified. Therefore, the role of GINS4 in LUAD was explored. MiR-133a-3p and GINS4 mRNA expression were tested through qRT-PCR. Protein levels of the two genes were assayed by western blot. Their targeting relationship was predicted and verified by bioinformatics prediction and dual-luciferase analysis. The functions of miR-133a-3p and GINS4 in LUAD were evaluated by Transwell, wound healing, CCK8 and flow cytometry assays. MTT assay and caspase-3 activity detection were utilized to measure the regulation of miR-133a-3p/GINS4 in the cisplatin sensitivity of LUAD cells. The results showed that GINS4 was highly expressed in LUAD cells (P<0.05). MiR-133a-3p, which was the upstream gene of GINS4 in LUAD, negatively mediated GINS4 expression. Moreover, overexpressing GINS4 enhanced the proliferative, migratory and invasive abilities of LUAD cells and inhibited cell apoptosis and the sensitivity to cisplatin, while overexpressed miR-133a-3p caused the contrary results. However, the promoting effects of GINS4 overexpression on LUAD could be offset by miR-133a-3p overexpression. MiR-133a-3p could regulate malignant behaviors and cisplatin sensitivity of LUAD cells through negatively regulating GINS4. In conclusion, our findings demonstrated that GINS4 was overexpressed in LUAD and promoted the malignant behavior of LUAD cells. Moreover, miR-133a-3p could negatively regulate GINS4, thereby suppressing the malignant progression and increasing the cisplatin sensitivity of LUAD.

Radiation recall pneumonitis triggered by an immune checkpoint inhibitor following re-irradiation in a lung cancer patient: a case report.

BACKGROUND: Radiation recall pneumonitis (RRP) is unpredictable but associated with severe radiation damage in previously irradiated fields. Chemotherapy and targeted drugs have been reported to contribute to RRP. Here we report a case of a patient with non-small cell lung cancer (NSCLC) who developed RRP following administration of immune checkpoint inhibitor (ICI) 18 months after the end of re-irradiation. CASE PRESENTATION: A 69-year-old man received adjuvant chemoradiotherapy post-operatively. He underwent thoracic re-irradiation for oligometastatic NSCLC. On second recurrence, pembrolizumab combined with nab-paclitaxel were administered. After six months, he developed symptoms of persistent cough and dyspnea, with consistent pneumonitis on CT images. The clinical time frame and significant radiographic evidence raised suspicion for RRP. Symptoms resolved after steroids. CONCLUSIONS: RRP is a rare occurrence. Patients undergoing immunotherapy after prior irradiation may be at increased risk of this rare radiation pneumonitis.