Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy

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Contributions of the NICHD neonatal research network's generic database to documenting and advancing the outcomes of extremely preterm infants

The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) maintains a database of extremely preterm infants known as the Generic Database (GDB). Begun in 1987, this database now includes more than 91,000 infants, most of whom are extremely preterm (<29 weeks gestation). The GDB has been the backbone of the NRN, providing high quality, prospectively collected data to study the changing epidemiology of extreme prematurity and its outcomes over time. In addition, GDB data have been used to generate hypotheses for prospective studies and to develop new clinical trials by providing information about the numbers and characteristics of available subjects and the expected event rates for conditions and complications to be studied. Since its inception, the GDB has been the basis of more than 200 publications in peer-reviewed journals, many of which have had a significant impact on the field of neonatology.     

刺槐素通过调控TLR4通路对干眼症大鼠的保护作用及其机制研究＊

目的 研究刺槐素对干眼症（DED）大鼠的保护作用及可能的分子机制。方法 60只SD大鼠随机分为空白组（不做处理）；模型组；0.1% SH组；刺槐素0.1%、0.25%、0.5%组。每组10只，除正常组外，每日4次皮下注射12.5 mg/天氢溴酸东莨菪碱（SCOP），共7天。所有的药物均为在眼球表面局部给药，每只眼睛20 μL，每天4次。通过泪液分泌实验检测各组大鼠泪液分泌情况，通过角膜荧光染色检测各组大鼠角膜表面缺损情况，过碘酸雪夫试剂（PAS）染色观察结膜杯状细胞数量，酶联免疫吸附法（ELISA）检测各组大鼠角膜组织中炎症反应和氧化应激相关指标含量。免疫印迹法（Western blot）检测各组大鼠角膜组织中Toll样受体4（TLR4）通路相关蛋白TLR4、髓样分化因子88（MyD88）、核因子κB p65（NF-κB p65）、Pyrin域蛋白3（NLRP3）蛋白表达。结果 与正常组相比，模型组大鼠泪液分泌量、结膜杯状细胞数量明显减少，角膜荧光素染色评分显著升高，但角膜新血管生成评分减少，同时角膜组织中白细胞介素1β（IL-1β）、肿瘤坏死因子α（TNF-α）、IL-10、丙二醛（MDA）水平上调，而超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）含量则下调，TLR4、MyD88、NLRP3、p-NF-κB p65蛋白相对表达量均升高（P<0.05）；与模型组相比，经刺槐素0.25%、0.5%组治疗后，大鼠泪液分泌量、结膜杯状细胞数量明显增加，角膜荧光素染色评分显著降低，角膜新血管生成评分显著增加，同时角膜组织中IL-1β、TNF-α、IL-10、MDA水平下调，而SOD和GSH-Px含量则上调（P<0.05），尤其是刺槐素0.5%组上述指标变化更明显，而且角膜组织中TLR4、MyD88、NLRP3、p-NF-κB p65蛋白相对表达量较模型组显著降低（P<0.05）。结论 刺槐素对干眼症大鼠具有保护作用，其保护机制与抑制干眼症大鼠的氧化应激反应、炎症反应和TLR4/MyD88/NLRP3通路活性有关。     

Methodological advances in the design of peptide-based vaccines

The tremendous advances in genomics, recombinant DNA technology, bioengineering and nanotechnology, in conjunction with the development of high-end computations, have been instrumental in the process of rational design of peptide-based vaccines. The use of peptide vaccines was limited owing to their inherent instability when systemically administered; however, advanced formulation techniques have been developed for their systemic delivery, thereby overcoming their degradation, clearance, cellular uptake and off-target effects. With the rise of sophisticated immunological predictors and experimental techniques, several methodological advances have occurred in this field. This review examines contemporary methods to identify and optimize epitopes, engineer their immunogenic properties and develop their safe and efficient delivery into the host.     

Maternal influenza vaccination and child mortality: Longitudinal,population-based linked cohort study

Influenza vaccination is recommended to protect mothers and their infants from influenza. Few studies have evaluated the association between maternal influenza vaccination and child mortality. We aimed to evaluate the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and mortality among young children. This longitudinal, population-based cohort study included 191,247 maternal-child pairs in Western Australia between April 2012 and December 2017. Maternal vaccine information was obtained from a state-wide antenatal vaccination database. Mortality was defined as a record of a death registration. We used Cox proportional hazard models, weighted by the inverse-probability of treatment (vaccination), to estimate the hazard ratio of child mortality associated with in utero exposure to seasonal IIV. This study found no association between in utero exposure to seasonal IIV and mortality through age five years.     

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

Diagnosis of pituitary abscess and treatment via transsphenoidal surgery: experience from 15 cases

ObjectivePituitary abscess is an often misdiagnosed, rare clinical disorder. To improve diagnostic accuracy and the efficacy of surgical and antibiotic therapy for patients with pituitary abscess, herein, we retrospectively reviewed 15 patients who presented with pituitary abscesses from 2005 to 2022.DesignRetrospective study.PatientsFifteen patients underwent transsphenoidal surgery and received antibiotic treatment.MeasurementsComplete details regarding medical history, clinical manifestations, laboratory examinations, imaging studies, and treatment strategies were obtained for all patients.ResultsMost patients presented with hypopituitarism and headaches, while some presented with fever, visual disturbances, and diabetes insipidus (DI). Abscesses showed significant annular enhancement post gadolinium injection. In most patients, pituitary abscess can be cured via microscopic or endoscopic drainage of the abscess followed by antibiotic treatment. Complete cure of pituitary abscess was observed in nine patients, with six cases of prolonged hypopituitarism and only one case of recurrence. Long-term hormone replacement therapy was effective in the postoperative management of hypopituitarism.ConclusionsThe typical manifestations of pituitary abscess include hypopituitarism and headaches; the presence of an enhanced ring at the edge of the mass on contrast-enhanced magnetic resonance images (MRI) is highly suggestive of pituitary abscess. We recommend antibiotic treatment for 4–6 weeks postoperatively, based on the results of bacterial cultures or metagenomic next-generation sequencing (mNGS).     

Evaluation of 5-aminolevulinic acid-mediated photodynamic therapy in postmenopausal women with persistent HPV infection with or without cervical and vaginal low-grade squamous intraepithelial lesions (CIN1/VaIN1)

ObjectiveTo analyze the efficacy and safety of photodynamic therapy (PDT) on postmenopausal women with persistent human papillomavirus (HPV) infection with or without low-grade cervical and vaginal intraepithelial neoplasia (CIN1 and VaIN1).Materials and methodsThe clinicopathological and follow-up data of 86 postmenopausal women with HPV infection (35 cases with chronic cervicitis and 51 cases with CIN1/VaIN1) were collected. All the women in this group met these criteria: menopausal time ≥ 1 year, HPV infection time ≥ 2 years, colposcopy and pathological diagnosis of biopsy ≤ CIN1/VaIN1 before PDT treatment, and 5-aminolaevulinic acid (5-ALA) as photosensitizer treating for 6 times with a week interval. The above patients were followed up 6 months and 12 months after PDT treatment, and the follow-up contents included HPV typing, cytology, colposcopy and pathological examinations. HPV negative conversion rate and lesion remission rate are the evaluation indicators of treatment efficacy. In addition, we also assessed the safety of PDT treatment.ResultsAt 12-month follow-up, the overall HPV clearance rate was 60% (45/75), of which the negative conversion rate of 16/18 HPV was 41.38% (12/29), and non-16/18 HPV was 71.74% (33/46) (p = 0.009). In patients without lesions, the HPV clearance rate was 51.72% (15/29), while in patients with CIN1/VaIN1 (n = 46), the HPV complete remission rate and lesion regression rate were 65.22% (30/46) and 89.13% (41/46), respectively. In addition, the clearance rate of HPV in lesion regression group was significantly higher than that in lesion persistence/progression group (0.00% vs. 73.17%, p = 0.003). The adverse reactions after PDT treatment were mild, mainly manifested as increased vaginal secretions or burning/tingling.ConclusionsPhotodynamic therapy can significantly enhance the elimination rate of persistent HPV infection in postmenopausal women and reduce the progression of CIN1/VaIN1. It could be an effective conservative treatment for persistent HPV infection and CIN1/VaIN1 in postmenopausal women.