First-in-human study to evaluate the safety, tolerability, and population pharmacokinetic/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects.

FL058 is a novel diazabicyclooctane ß-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).

IL-10-producing B cells in differentiated thyroid cancer suppress the effector function of T cells but improve their survival upon activation.

Despite having favorable prognosis, patients with differentiated thyroid carcinoma (DTC) still suffer from reduced lifespan due to recurrences, metastasis, and dedifferentiation. Regulatory B (Breg) cells are essential to the maintenance of peripheral tolerance, but upregulated Breg response may impede the clearance of pathogens and tumor cells. Here, we found that in PBMCs, the frequency of IL-10+ circulating B cells ex vivo and following stimulation was similar between DTC patients and healthy controls. However, in resected tumor, the frequency of IL-10+ B cells was significantly elevated and was positively correlated with the frequency of tumor-infiltrating CD4+Foxp3+ T cells. The quantity of IL-10 produced by B cells was significantly higher in DTC patients than in controls. Moreover, each IL-10-producing B cell in DTC patients produced more IL-10 than the counterparts in healthy controls. This IL-10+ subset was enriched in the CD27+ fraction. Under an in vitro setting, CD27+ B cells inhibited IFN-γ expression from CD4+ T cells and IFN-γ, perforin, and granzyme B expression from CD8+ T cells. Suppression of IL-10 could rescue IFN-γ production but was unable to completely rescue perforin and granzyme B expression. The proliferation of CD4+ and CD8+ T cells, on the other hand, was not affected by CD27+ B cells. Interestingly, CD27+ B cells improved the survival of activated CD4+ and CD8+ T cells, in an IL-10-dependent manner. In addition, the phosphorylation level of STAT3 and Erk was examined in CD27+ B cells. Unstimulated CD27+ B cells presented low STAT3 and Erk phosphorylation in both healthy controls and DTC patients, with no significant difference between the two groups. Overall, this study suggests that B cell-mediated IL-10 production can exert complex effects toward autologous T cells.

Prognostic factors in children and adolescents with differentiated thyroid cancer treated with total thyroidectomy and radioiodine therapy: a retrospective two-center study from China.

Purpose: This two-center study aimed to explore the main prognostic factors affecting the final disease status in children and adolescents with differentiated thyroid cancer (caDTC) following total thyroidectomy and radioiodine therapy (RAIT). Materials and methods: All caDTC patients from two centers in the period from 2004-2022 were retrospectively included. At the last follow-up, the patients' disease status was assessed and classified as an incomplete response (IR) or as an excellent or indeterminate response (EIDR). Then, the difference in preablation stimulated thyroglobulin (ps-Tg) levels between the two groups was compared, and the threshold for predicting IR was determined using receiver operating characteristic (ROC) analysis. Moreover, univariate and multivariate analyses were conducted to identify the factors influencing the patients' ultimate disease outcomes. Results: A total of 143 patients (98 females, 45 males; median age 16 years) were recruited. After a median follow-up of 42.9 months, 80 patients (55.9%) exhibited an EIDR, whereas 63 patients (44.1%) exhibited an IR. Patients with an IR had significantly greater ps-Tg levels than did those with an EIDR (median ps-Tg 79.2 ng/mL vs. 9.3 ng/mL, p<0.001). The ROC curve showed that ps-Tg ≥20 ng/mL was the most accurate for predicting IR at the last follow-up. According to multivariate analysis, only ps-Tg, T stage and the therapeutic response to initial RAIT were significantly associated with IR. Conclusion: In caDTC patients, the ps-Tg level, T stage, and response to initial RAIT are critical final outcome indicators.

Efficacy and Safety of Biosimilar QL1207 vs. the Reference Aflibercept for Patients with Neovascular Age-Related Macular Degeneration: A Randomized Phase 3 Trial.

INTRODUCTION: This trial aimed to compare the efficacy and safety between biosimilar QL1207 and the reference aflibercept for the treatment of neovascular age-related macular degeneration (nAMD). METHODS: This randomized, double-blind, phase 3 trial was conducted at 35 centers in China. Patients aged ≥ 50 years old with untreated subfoveal choroidal neovascularization secondary to nAMD and best-corrected visual acuity (BCVA) letter score of 73-34 were eligible. Patients were randomly assigned to receive intravitreous injections of QL1207 or aflibercept 2 mg (0.05 ml) in the study eye every 4 weeks for the first 3 months, followed by 2 mg every 8 weeks until week 48, stratified by baseline BCVA ≥ or < 45 letters. The primary endpoint was BCVA change from baseline at week 12. The equivalence margin was ± 5 letters. The safety, immunogenicity, pharmacokinetics (PK), and plasma vascular endothelial growth factor (VEGF) concentration were also evaluated. RESULTS: A total of 366 patients were enrolled (QL1207 group, n = 185; aflibercept group, n = 181) from Aug 2019 to Jan 2022 with comparable baseline characteristics. The least-squares mean difference in BCVA changes was - 1.1 letters (95% confidence interval - 3.0 to 0.7; P = 0.2275) between the two groups, within the equivalence margin. The incidences of treatment-emergent adverse events (TEAE; QL1207: 71.4% [132/185] vs. aflibercept: 71.8% [130/181]) and serious TEAE (QL1207: 14.1% [26] vs. aflibercept: 12.7% [23]) appeared comparable between treatment groups, and no new safety signal was found. Anti-drug antibody, PK profiles, and VEGF concentration were similar between the two groups. CONCLUSIONS: QL1207 has equivalent efficacy to aflibercept for nAMD with similar safety profiles. It could be used as an alternative anti-VEGF agent for clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05345236 (retrospectively registered on April 25, 2022); National Medical Products Administration of China: CTR20190937 (May 20, 2019).

Stimulated thyroglobulin and pre-ablation antithyroglobulin antibody products can predict the response to radioiodine therapy of TgAb-positive differentiated thyroid cancer patients: a retrospective study.

Objective: We aimed to explore the predictive value of stimulated thyroglobulin (sTg) and pre-ablation antithyroglobulin (pa-TgAb) products for the effect of radioiodine therapy (RAIT) on TgAb-positive differentiated thyroid cancer (DTC) patients. Methods: In this study, we enrolled 265 patients with TgAb-positive DTC who underwent RAIT after total thyroidectomy (TT). Based on the last follow-up result, the patients were divided into two groups: the excellent response (ER) group and the non-excellent response (NER) group. We analyzed the factors related to the effect of RAIT. Results: The ER group consisted of 197 patients. The NER group consisted of 68 patients. For the univariate analysis, we found that the maximal tumor diameter, whether with extrathyroidal extension (ETE), bilateral or unilateral primary lesion, multifocality, preoperative TgAb (preop-TgAb), pa-TgAb, sTg × pa-TgAb, initial RAIT dose, N stage, and surgical extent (modified radical neck dissection or not), showed significant differences between the ER group and NER group (all p-values <0.05). The receiver operating characteristic (ROC) curves showed that the cutoff value was 724.25 IU/ml, 424.00 IU/ml, and 59.73 for preop-TgAb, pa-TgAb, and sTg × pa-TgAb, respectively. The multivariate logistic regression analysis results indicated that pa-TgAb, sTg × pa-TgAb, initial RAIT dose, and N stage were independent risk factors for NER (all p-values <0.05). For the Kaplan-Meier analysis of disease-free survival (DFS), the median DFS of the patients with sTg × pa-TgAb < 59.73 and initial RAIT dose ≤ 100 mCi was significantly longer than that of the patients with sTg × pa-TgAb ≥ 59.73 (50.27 months vs. 48.59 months, p = 0.041) and initial RAIT dose >100 mCi (50.50 months vs. 38.00 months, p = 0.030). Conclusion: We found the sTg and pa-TgAb conducts is a good predictor of the efficacy of RAIT in TgAb-positive DTC patients. It can play a very positive and important role in optimizing treatment, improving prognosis, and reducing the burden of patients.

Efficacy evaluation and influencing factor analysis of postoperative 131I for the treatment of primary hyperthyroidism combined with differentiated thyroid cancer (DTC)-a retrospective cohort study.

Background: 131I treatment is one of the important methods of comprehensive postoperative treatment for patients with hyperthyroidism complicated with differentiated thyroid cancer (DTC). Early identification of patients with poor treatment efficacy of 131I is particularly important. Current studies mainly focus on the relationship between hyperthyroidism and the occurrence and development of DTC, and there are few studies on the factors affecting the curative effect. The purpose of this study was to find the influencing factors of efficacy evaluation and provide evidence for early identification of patients with poor efficacy in DTC combined with primary hyperthyroidism patients. Methods: This was a retrospective analysis of DTC patients with primary hyperthyroidism who received 131I treatment in our department from 2012 to 2021. Follow-up intervals were 3 months within 1 year, 6 months within 1 to 2 years, and annual follow-up thereafter, the median follow-up time was 12.0 (3.0, 24.0) months. Serological examination and imaging examination were used to evaluate the efficacy. Patients were classified into an excellent response (ER) group and a non-ER group based on treatment response more than 6 months after 131I treatment. Univariate analysis and multivariate logistic regression analysis were performed on the basic clinical characteristics, pathological characteristics and curative effect of the patients, in order to find independent risk factors affecting the curative effect. Results: Eighty-nine patients were mostly female (80.9%), the average age was 43.47±11.88 years old, and tumor size was 1.2 (0.75, 1.80) cm, 56 patients (62.9%) in the ER group. psTg [odds ratio (OR): 1.325; 95% confidence interval (CI): 1.135-1.547; P<0.001], maximum tumor diameter (OR: 2.428; 95% CI: 1.392-4.235; P=0.002) and pathology-confirmed combined HT (OR: 8.669; 95% CI: 1.877-40.038; P=0.006) were independent risk factors for predicting ER. Conclusions: Our findings demonstrate that most hyperthyroidism combined with DTC patients could get favorable clinical outcomes from 131I treatment. The tumor diameter, pathology-confirmed diagnosis of combined HT, and psTg level can be used to identify patients who can get ER by the effect of 131I in hyperthyroidism combined with DTC at an early stage.

The influence of stimulated thyroglobulin and lymphocyte subsets before radioiodine therapy on the therapeutic response in patients with intermediate- and high-risk papillary thyroid carcinoma.

The aim of the present study was to investigate the factors influencing the short-term response to the initial radioiodine therapy (RT) course in patients with intermediate- and high-risk papillary thyroid carcinoma (PTC). A total of 182 patients with intermediate- and high-risk PTC who underwent RT in our hospital from March 2018 to October 2020 were retrospectively enrolled. The patients were divided into incomplete response (IR) and nonincomplete response (Non-IR) groups according to the response observed in clinical follow-up within 6-12 months after RT. Univariate and multivariate logistic regression analyses were used to investigate the effects of 15 observed factors on the response to RT. Receiver operating characteristic (ROC) curve analysis was used to determine the value of factors found to be significant in multivariate analyses for predicting an IR. A total of 182 patients with intermediate- and high-risk PTC were analyzed; the percentage of patients with a Non-IR was 61.54% (112/182), and the percentage of patients with an IR was 38.46% (70/182). The CD4+ T-cell percentage (t = 4.757, P = 0.000), CD4/CD8 (z = - 2.632, P = 0.008), stimulated thyroglobulin (sTg) level (z = - 8.273, P = 0.000) and M stage (χ2 = 17.823, P = 0.000) of the two groups were significantly different. Multivariate analysis showed that only the sTg level (OR: 1.116, 95% CI 1.068-1.165, P < 0.001) and CD4+ T-cell percentage (OR: 0.909, 95% CI 0.854-0.968, P = 0.003) were independent factors associated with the therapeutic response to RT. The cutoff sTg level and CD4+ T-cell percentage for predicting an IR were 7.62 µg/L and 40.95%, respectively. The sTg level and CD4+ T-cell percentage were verified to be independent predictive factors of RT response. Higher sTg levels and lower CD4+ T-cell percentages were related to an IR in patients with intermediate- and high-risk PTC.

Recovering partial nitritation in a PN/A system during mainstream wastewater treatment by reviving AOB activity after thoroughly inhibiting AOB and NOB with free nitrous acid.

Starting up or recovering partial nitritation is a major challenge for achieving or maintaining stable partial nitritation/anammox (PN/A) during mainstream wastewater treatment. This study presents a novel strategy for recovering the nitrite pathway by selectively reviving ammonium oxidizing bacteria (AOB) after thoroughly inhibiting AOB and nitrite oxidizing bacteria (NOB) using free nitrous acid (FNA). A sequencing batch reactor was operated for PN/A to treat real domestic wastewater for 423 days, during which twice FNA treatment was temporarily implemented. Results showed that with a single 0.45 mg/L FNA treatment on flocculent sludge, the NO3--N concentration during the aerobic period showed an uptrend again and the partial nitritation performance was deteriorated. In contrast, 1.35 mg/L FNA treatment induced the inhibition of both AOB and NOB leading to regressive ammonium oxidation, but a subsequently higher DO (1.5 mg/L) and longer aeration duration recovered partial nitritation. For the relative abundances of the acquired biomass related to nitrogen conversion, Nitrosomonas, Nitrospira and Nitrolancea increased to 9.65%, 10.27% and 4.35%, respectively, at the beginning of the 1.35 mg/L FNA treatment, and Nitrospira and Nitrolancea decreased to 2.80% and 0.03% whereas Nitrosomonas declined to 8.71% after 76 days. Ca. Brocadia showed less resilience after the 1.35 mg/L FNA treatment, with the relative abundance decreasing from 13.38% to 0.62% due to insufficient nitrite. Molecular ecological network analysis indicates that among anammox taxa, Ca. Kuenenia and Ca. Brocadia formed important links with other N cycle processes. Moreover, the proposed strategy shows operational flexibility because it can be easily used to control NOB in mainstream PN/A applications offered by flocculent sludge systems.

Free nitrous acid pretreatment of sludge to achieve nitritation: The effect of sludge concentration.

This study investigated the effect of sludge concentration (expressed by mixed liquor volatile suspended solids, MLVSS) on free nitrous acid (FNA) pretreatment strategy to achieve nitritation. Results showed when FNA was 0.308 mgHNO2-N/L, nitrite oxidizing bacteria (NOB) activity increased by 70.2% as MLVSS increased from 8.4 to 16.8 g/L. Nitrite accumulation ceased as MLVSS increased to 12.6 g/L, indicating that FNA inhibition of NOB gradually weakened with increasing MLVSS. When FNA was higher than 0.770 mgHNO2-N/L, NOB activity was completely inhibited and the effect of MLVSS on FNA inhibition was negligible, with nitrite accumulation potential (NAP) varying from 88.1% to 90.0%. Mechanism investigation demonstrated flocs sizes distinctly declined, with more extracellular polymeric substances (EPS) released to resist FNA inactivation. Linear fitting showed NAP increased with FNA/MLVSS increment. Therefore, MLVSS affected FNA pretreatment performance, with FNA/MLVSS proposed as a more valuable criterion in FNA pretreatment strategy development, than the solely FNA.

The efficacy of 99mTc-MIBI imaging in 125I seed implantation treatment of rabbit VX2 transplanted liver cancer.

PURPOSE: To evaluate the efficacy of 99mTc-MIBI imaging in the evaluation of 125I radioactive particle implantation for treatment of rabbit VX2 transplanted liver cancer. METHODS: Twelve New Zealand white rabbit VX2 liver cancer models were successfully prepared by tumor cell suspension method and randomly divided into a control group and treatment group. The treatment group received 125I particle implantation according to the TPS plan, and the control group received the same number of hollow particle implantation. 99mTc-MIBI imaging was performed before and 7 d, 14 d, and 28 d after implantation. The target lesion (target, T) and normal liver tissue (nontarget, N) were determined by region of interest (ROI) technique. Radioactivity count was used to calculate the 99mTc-MIBI uptake ratio (target-to-nontarget ratio, T/N) between the target lesion and normal liver tissue, thereby obtaining early ratio (ER) and delayed ratio (DR), respectively. The retention index (RI) was calculated. The mice were sacrificed after 28 days for histopathologic observation. RESULTS: The T/N ratio, ER, and DR showed no statistical changes following the implantation time in the control group. In the treatment group, ER and DR gradually decreased after implantation of 125I seeds (P < 0.05). There was no significant difference in RI during different observation times between the treatment group and the control group. Compared with the treatment group, RI exhibited no statistical difference between before and 7 d, 7~14 d, and 14~28 d after implantation (P > 0.05). CONCLUSION: This method has value in evaluating the efficacy of 125I seed implantation treatment of rabbit VX2 transplanted liver cancer. The T/N ratio is independent of the tumor diameter, but is related to the blood perfusion and metabolic state of the tumor. Implantation of 125I particles into the rabbit transplanted liver cancer can effectively inhibit tumor growth, thus is a safe and effective method.

PD-1-expressing B cells suppress CD4+ and CD8+ T cells via PD-1/PD-L1-dependent pathway.

B cell-mediated regulatory function is instrumental to the maintenance of tolerance, but may also contribute to immune dysfunction during infectious diseases and malignancies. In this study, we investigated a subset of B cells characterized by PD-1 expression. Data showed that these PD-1+ B cells were rare in peripheral blood, but were significantly upregulated in differentiated thyroid tumors. The PD-1+ B cells also expressed significantly higher level of PD-L1. Continuous, but not short-term, anti-Ig/CD40 L stimulation could upregulate the expression of PD-1 and PD-L1 in B cells. In in vitro experiments, PD-1+ B cells significantly suppressed the proliferation of CD4+ and CD8+ T cells and reduced their viability upon CD3/CD28 stimulation, thus suggesting that these PD-1+ B cells presented regulatory functions. However, unlike other IL-10-secreting Breg cell subsets, the PD-1+ B cells did not express high level of IL-10. Instead, it seemed that PD-L1 was instrumental to the suppressive effects mediated by PD-1+ B cells, since the blockade of PD-L1 significantly increased the proliferation and viability of T cells in the coculture. Interestingly, compared to untreated patients with differentiated thyroid tumor, the thyroidectomy and 131I-treated patients presented significantly lower frequencies of PD-1+ B cells. Together, our investigation demonstrated that the PD-1+ B cells possessed regulatory capacity toward T cell responses, and although rare in peripheral blood, they were significantly enriched in thyroid tumors.

Highly crystalline Nb-doped TiO2 nanospindles as superior electron transporting materials for high-performance planar structured perovskite solar cells.

Planar-structured perovskite solar cells (PSCs) have received tremendous attention due to their high power conversion efficiency (PCE), simple process and low-cost fabrication. A compact thin film of electron transport materials (ETMs) plays a key role in these PSCs. However, the traditional ETMs of PSCs, TiO2 nanoparticulate films, suffer from low conductivity and high trap state density. Herein, we exploited TiO2 nanospindles as a compact ETM in planar PSCs for the first time, and achieved an efficient device with a PCE of 19.1%. By optimization with Nb doping into the TiO2 nanospindles, the PCE of the PSC was further improved up to 20.8%. The carrier transfer and collection efficiency were significantly improved after Nb5+ doping, revealed by Mott-Schottky (MS) analysis, space charge limited current (SCLC), photoluminence (PL), time-resolved photoluminence (TRPL) spectra, electrochemical impedance spectra (EIS) and so forth. Moreover, the hysteresis behavior was effectively inhibited and the stability was significantly enhanced. This work may provide a new avenue towards the rational design of efficient ETMs for perovskite solar cells.

Heterojunction Engineering for High Efficiency Cesium Formamidinium Double-Cation Lead Halide Perovskite Solar Cells.

It is essential to minimize the interfacial trap states and improve the carrier collection for high efficiency perovskite solar cells (PSCs). Herein, we present a facile method to construct a p-type graded heterojunction (GHJ) in normal PSCs by deploying a gradient distribution of hole-transporting materials (poly[bis(4-phenyl)(2,4,6-trimethylphenyl)amine], PTAA, in this case) in the shallow perovskite layer. The formation of the GHJ structure facilitates charge transfer and collection, and passivates interfacial trap states, thus delivering a power conversion efficiency (PCE) of 20.05 % along with steady output efficiency of 19.3 %, which is among the highest efficiencies for cesium formamidinium (Cs-FA) lead halide PSCs. Moreover, the unencapsulated devices based on these (Cs-FA) lead halide perovskites show excellent long-term stability; more than 95 % of their initial PCE can be retained after 1440 h storage under ambient conditions. This study may provide an effective strategy to fabricate high-efficiency PSCs with great stability.

Superior mediastinal typical carcinoid detected by 99mTc-MIBI SPECT/CT imaging: A case report.

RATIONALE: This is a rare case of mediastinal typical carcinoid tumor with elevated parathyroid hormone (PTH) and hypercalcemia detected by Tc -methoxy-isobutyl-isonitrile(Tc-MIBI) single photon emission computed tomography/computed tomography (SPECT/CT) imaging. PATIENT CONCERNS: A 65-year-old male patient presented with hypercalcemia and elevated PTH. DIAGNOSES: The preoperative diagnosis was ectopic parathyroid adenoma in the right superior mediastinum. INTERVENTIONS: We performed endoscopic removal of the mass in the superior mediastinum. OUTCOMES: Histopathology and immunohistochemistry revealed typical carcinoid. LESSONS: The differential diagnosis of mediastinal tumors with elevated PTH detected by Tc-MIBI dual-phase imaging should include ectopic parathyroid adenoma as well as carcinoid.

A new kind of transparent and self-cleaning film for solar cells.

A kind of one step and in situ etching method is developed to fabricate a highly optically transparent and flexible self-cleaning superhydrophobic film (SSF). This SSF exhibits a very rough surface morphology with hierarchical structure, which makes it have a contact angle of 154.6° and a sliding angle of smaller than 1°. And the SSF can also be self-cleaned in the wind. The SSF hierarchical structure scatters the incident light, but it almost doesn't attenuate the light. So the SSF has antireflection properties and a high light transmittance of 94%. The excellent self-cleaning property, high light transmittance and antireflection property mean that the SSF greatly enhances the performance of solar cells in practical working conditions. The solar cell's efficiency maintains at 95.8% of its initial value after covering with the SSF, which is about 1.7 times higher than that of the solar cell covered with dust, as in practical conditions.