Immune checkpoint inhibitor for different age patients with NSCLC in efficacy: A systematic review and meta-analysis.

OBJECTIVE: This article is a Meta-analysis aiming to systematically evaluate the difference in efficacy of immune checkpoint inhibitor in patients with non-small cell lung cancer (NSCLC) by age. METHODS: We performed a Meta-analysis of published randomized controlled trials concerning for patients with NSCLC by age. We compared overall survival among three groups (age <65 years, age 65-75 years, age ≥75 years). Hazard ratios (HRs) and 95% confidence intervals (CIs) were collected and pooled. RESULTS: A total of 10,291 patients from 17 RCTs were included. In the group under age 65 years, immune checkpoint inhibitor can significantly prolong the overall survival of patients with NSCLC (HR = 0.73, 95% CI: 0.66∼0.81, P < 0.00001). In the age 65-75 years group, immune checkpoint inhibitors prolonged overall survival in patients with NSCLC (HR = 0.78, 95% CI:0.71∼0.84, P < 0.00001). However, it has no significant effect on the overall survival of NSCLC patients (HR = 0.88, 95% CI:0.72∼1.08, P > 0.05) in the group older than 75 years. CONCLUSIONS: Immune checkpoint inhibitors prolonged the overall survival of NSCLC patients in the age <65 years group and the age 65-75 years group, but in the age ≥75 years group, there was no significant effect on overall survival. This may be related to innate immune and adaptive immune dysregulation due to "immunosenescence" in older patients.

SESAM mode-locked Yb:GdScO3 laser.

We report on the investigation of continuous-wave (CW) and SEmiconductor Saturable Absorber Mirror (SESAM) mode-locked operation of a Yb:GdScO3 laser. Using a single-transverse-mode, fiber-coupled InGaAs laser diode at 976 nm as a pump source, the Yb:GdScO3 laser delivers 343 mW output power at 1062 nm in the CW regime, which corresponds to a slope efficiency of 52%. Continuous tuning is possible across a wavelength range of 84 nm (1027-1111 nm). Using a commercial SESAM to initiate mode-locking and stabilize soliton-type pulse shaping, the Yb:GdScO3 laser produces pulses as short as 42 fs at 1065.9 nm, with an average output power of 40 mW at 66.89 MHz. To the best of our knowledge, this is the first demonstration of passively mode-locking with Yb:GdScO3 crystal.

Structurally diverse cucurbitane-type triterpenoids from the tubers of Hemsleya chinensis with cytotoxic activity.

Ten previously undescribed cucurbitane-type triterpenoids, namely hemslyencins A-F (1-6) and hemslyencosides A-D (7-10), together with twenty previously reported compounds (11-30), were isolated from the tubers of Hemsleya chinensis. Their structures were elucidated by unambiguous spectroscopic data (UV, IR, HR-ESI-MS, 1D and 2D NMR data). Hemslyencins A and B (1 and 2) possessing unique 9, 11-seco-ring system with a six-membered lactone moiety, were the first examples among of the cucurbitane-type triterpenoids, and hemslyencins C and D (3 and 4) and hemslyencoside D (10) are the infrequent pentacyclic cucurbitane triterpenes featuring a 6/6/6/5/6 fused system. The cytotoxic activities of all isolated compounds were evaluated against MCF-7, HCT-116, HeLa, and HepG2 cancer cells, and their structure-activity relationships (SARs) was discussed as well. Compounds 17, 25, and 26 showed significant cytotoxic effects with IC50 values ranging from 1.31 to 9.89 µM, among which compound 25 induced both apoptosis and cell cycle arrest at G2/M phase in a dose dependent manner against MCF-7 cells.

Intracytoplasmic sperm injection versus conventional in-vitro fertilisation for couples with infertility with non-severe male factor: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Introduced in 1992, intracytoplasmic sperm injection (ICSI) was initially indicated for severe male infertility; however, its use has since been expanded to non-severe male infertility. We aimed to compare the efficacy and safety of ICSI versus conventional in-vitro fertilisation (IVF) in couples with infertility with non-severe male factor. METHODS: We conducted an investigator-initiated, multicentre, open-label, randomised controlled trial in ten reproductive medicine centres across China. Couples with infertility with non-severe male factor without a history of poor fertilisation were randomly assigned (1:1) to undergo either ICSI or conventional IVF. The primary outcome was live birth after first embryo transfer. We performed the primary analysis in the intention-to-treat population using log-binomial regression models for categorical outcomes or linear regression models for continuous outcomes, adjusting for centre. This trial is registered with Clinicaltrials.gov, NCT03298633, and is completed. FINDINGS: Between April 4, 2018, and Nov 15, 2021, 3879 couples were screened, of whom 2387 (61·5%) couples were randomly assigned (1184 [49·6%] to the ICSI group and 1203 [50·4%] to the conventional IVF group). After excluding couples who were ineligible, randomised twice, or withdrew consent, 1154 (97·5%) in the ICSI group and 1175 (97·7%) in the conventional IVF group were included in the primary analysis. Live birth after first embryo transfer occurred in 390 (33·8%) couples in the ICSI group and in 430 (36·6%) couples in the conventional IVF group (adjusted risk ratio [RR] 0·92 [95% CI 0·83-1·03]; p=0·16). Two (0·2%) neonatal deaths were reported in the ICSI group and one (0·1%) in the conventional IVF group. INTERPRETATION: In couples with infertility with non-severe male factor, ICSI did not improve live birth rate compared with conventional IVF. Given that ICSI is an invasive procedure associated with additional costs and potential increased risks to offspring health, routine use is not recommended in this population. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Beijing Municipal Science & Technology Commission, and Peking University Third Hospital.

iRGD mediated pH-responsive mesoporous silica enhances drug accumulation in tumors.

The limited penetration of nanocarriers into tumors and the slow release of drugs from these carriers to tumor cells are significant challenges in cancer therapy. In this study, we developed a novel drug delivery carrier derived from mesoporous silica, dually modified with the tumor-homing cyclic peptide iRGD (CRGDKGPDC) and the pH-responsive polymer poly(2-ethyl-2-oxazoline) (PEOz) for treating triple-negative breast cancer. The carrier selectively bound to the αvß3 integrin receptor, which is specifically expressed in MDA-MB-231 breast cancer cells and vessels. Subsequently, it penetrated deep into the tumor parenchyma through NRP-1 receptor-dependent internalization, with the drug-loaded particles releasing drugs rapidly in the acidic cytoplasmic environment. Results indicated that the drug release rate of PEOz-modified formulations was pH-dependent. Lysosomal escape experiments demonstrated that PEOz-modified particles efficiently escaped lysosomes to release drugs. In vitro cytotoxicity assays revealed that iRGD-functionalized particles were more cytotoxic to NRP-1-positive MDA-MB-231 cells compared to NRP-1-negative MCF-7 cells. Cellular uptake studies demonstrated that iRGD mediated enhanced endocytosis of nanoparticles into MDA-MB-231 cells. In vitro tumor cell spheroid penetration assays confirmed that the PEOz and iRGD dual-modified carrier facilitated deeper distribution of DOX in multicellular spheroids compared to free DOX. Moreover, in a nude mouse model of triple-negative breast cancer, the dual-modified drug-loaded carrier significantly inhibited tumor growth without inducing weight loss or liver and kidney damage. This dual-modified mesoporous silica presents a novel and promising delivery carrier for enhancing cancer treatment.

Characteristics of broadband OPCPA based on DKDP crystals with different deuterations for the SEL-100 PW laser system.

We present the performances of a broadband optical parametric chirped pulse amplification (OPCPA) using partially deuterated potassium dihydrogen phosphate (DKDP) crystals with deuteration levels of 70% and 98%. When pumped by a Nd:glass double frequency laser, the OPCPA system using the 98% deuterated DKDP crystal achieves a broad bandwidth of 189 nm (full width at 1/e2 maximum) from 836 nm to 1025 nm. For the DKDP crystal with length of 43 mm, the pump-to-signal conversion efficiency reaches 28.4% and the compressed pulse duration is 13.7 fs. For a 70% deuterated DKDP crystal with a length of 30 mm, the amplified spectrum ranges from 846-1021 nm, the compressed pulse duration is 15.7 fs, and the conversion efficiency is 25.5%. These results demonstrate the potential of DKDP crystals with higher deuteration as promising nonlinear crystals for use as final amplifiers in 100 Petawatt (PW) laser systems, supporting compression pulse duration shorter than 15 fs.

Neurotrophin-4 promotes in vitro development and maturation of human secondary follicles yielding metaphase II oocytes and successful blastocyst formation.

STUDY QUESTION: Does a matrix-free culture system supplemented with neurotrophic factor 4 (NT4) improve human in vitro follicular development and meiotic maturation, ultimately resulting in fertilizable oocytes? SUMMARY ANSWER: NT4 supplementation of in vitro culture significantly enhances the growth, steroid hormone production, and maturity potential of human secondary follicles derived from fresh ovarian medulla (from post- and pre-pubertal patients), thereby yielding fertilizable oocytes. WHAT IS KNOWN ALREADY: Reconstituting folliculogenesis in vitro is of paramount importance in the realms of fertility preservation, reproductive biology research, and reproductive toxicity assessments. However, the efficiency of in vitro culture systems remains suboptimal, as the attainment of fertilizable oocytes from in vitro growth (IVG) of human follicles remains unachieved, with the data being particularly scant regarding follicles from prepubertal girls. We have previously found that mouse oocytes from secondary follicles derived from IVG are deficient in neuroendocrine regulation. NT4 and its corresponding receptor have been identified in human follicles. Significantly, the addition of NT4 during the IVG process markedly enhances both follicle growth and oocyte maturation rates in mice. STUDY DESIGN SIZE DURATION: Fresh medulla tissue obtained during tissue preparation for ovarian tissue cryopreservation (OTC) were collected from 10 patients aged from 6 to 21 years old, all of whom had undergone unilateral oophorectomy as a means of fertility preservation. Isolated secondary follicles were individually cultured in vitro with or without NT4 in a matrix-free system. PARTICIPANTS/MATERIALS SETTING METHODS: Secondary follicles, extracted via enzymatic digestion and mechanical disruption from each patient, were randomly allocated to either a control group or an NT4-supplemented group (100 ng/ml), followed by individual culture on an ultra-low attachment plate. Follicle growth and viability were assessed by microscopy. Levels of anti-Müllerian hormone (AMH), estradiol, and progesterone in the medium were quantified. An oocyte-specific marker was identified using confocal fluorescence microscopy following DEAD box polypeptide 4 (DDX4) staining. The competence of individual oocytes for maturation and fertilization were assessed after IVM and ICSI with donated sperm samples. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, isolated follicles from both groups survived up to 6 weeks with increasing diameters over the duration (P < 0.05), reaching terminal diameters of almost 1 mm with confirmed steroidogenesis and expression of oocyte marker (DDX4), and producing morphologically normal MII oocytes. When compared with the control group, the NT4 group had a similar initial follicular diameter (206 ± 61.3 vs 184 ± 93.4 µm) but exhibited a significant increase in follicular diameter from the ninth day of culture onwards (P < 0.05). From Week 3, estradiol and progesterone production were significantly increased in the NT4 group, while no significant difference was observed in AMH production between groups. The proportion of 'fast-growth' follicles in the NT4 group was significantly higher than that in the control group (13/23 vs 6/24, P < 0.05). An increased efficiency of MII oocyte maturation per live follicle in the NT4 group was also observed (control group vs NT4 group, 4/24 vs 10/23, P < 0.05). It is noteworthy that an MII oocyte obtained from the control group exhibited abnormal fertilization after ICSI. In contrast, an MII oocyte acquired from the NT4 group progressed to the blastocyst stage and showed potential for transfer. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The cohort examined in this study was all patients diagnosed with beta-thalassemia major. Whether this culture system is effective for patients with other diseases remains unknown. Since the chosen dose of NT4 was established based on dose finding in mice, the optimal dose for use in a human IVG system needs further confirmation. The oocytes and embryos procured from this study have not been quantified for ploidy status or epigenetic signatures. WIDER IMPLICATIONS OF THE FINDINGS: Fresh medulla tissue obtained during tissue preparation for OTC may serve as a precious source of fertilizable oocytes for female fertility preservation, even for pre-pubertal girls, without the threat of tumour reintroduction. After further characterization and optimization of the system, this culture system holds the potential to provide a powerful future research tool, for the comprehensive exploration of human follicular development mechanisms and for conducting reproductive toxicity evaluations. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Key R&D Program of China (grant number 2022YFC2703000) and National Natural Science Foundation of China (grant numbers 82271651 and 81871214). The medium used in human follicle in vitro culture in this study has been applied for a national invention patent in China (No. 202211330660.7). The inventors of the patent, in order, are: Y.G., C.F., and X.L.

Global crotonylome identifies EP300-regulated ANXA2 crotonylation in cumulus cells as a regulator of oocyte maturation.

Lysine crotonylation (Kcr), a newly discovered post-translational modification, played a crucial role in physiology and disease progression. However, the roles of crotonylation in oocyte meiotic resumption remain elusive. As abnormal cumulus cell development will cause oocyte maturation arrest and female infertility, we report that cumulus cells surrounding human meiotic arrested oocytes showed significantly lower crotonylation, which was associated with decreased EP300 expression and blocked cumulus cell expansion. In cultured human cumulus cells, exogenous crotonylation or EP300 activator promoted cell proliferation and reduced cell apoptosis, whereas EP300 knockdown induced the opposite effect. Transcriptome profiling analysis in human cumulus cells indicated that functions of crotonylation were associated with activation of epidermal growth factor receptor (EGFR) pathway. Importantly, we characterized the Kcr proteomics landscape in cumulus cells by LC-MS/MS analysis, and identified that annexin A2 (ANXA2) was crotonylated in cumulus cells in an EP300-dependent manner. Crotonylation of ANXA2 enhanced the ANXA2-EGFR binding, and then activated the EGFR pathway to affect cumulus cell proliferation and apoptosis. Using mouse oocytes IVM model and EP300 knockout mice, we further confirmed that crotonylation alteration in cumulus cells affected the oocyte maturation. Together, our results indicated that EP300-mediated crotonylation is important for cumulus cells functions and oocyte maturation.

Single-Cell Atlas of Human Ovaries Reveals The Role Of The Pyroptotic Macrophage in Ovarian Aging.

Female fecundity declines in a nonlinear manner with age during the reproductive years, even as ovulatory cycles continue, which reduces female fertility, disrupts metabolic homeostasis, and eventually induces various chronic diseases. Despite this, the aging-related cellular and molecular changes in human ovaries that occur during these reproductive years have not been elucidated. Here, single-cell RNA sequencing (scRNA-seq) of human ovaries is performed from different childbearing ages and reveals that the activation of the pyroptosis pathway increased with age, mainly in macrophages. The enrichment of pyroptotic macrophages leads to a switch from a tissue-resident macrophage (TRM)-involve immunoregulatory microenvironment in young ovaries to a pyroptotic monocyte-derived macrophage (MDM)-involved proinflammatory microenvironment in middle-aged ovaries. This remolded ovarian immuno-microenvironment further promotes stromal cell senescence and accelerated reproductive decline. This hypothesis is validated in a series of cell and animal experiments using GSDMD-KO mice. In conclusion, the work expands the current understanding of the ovarian aging process by illustrating a pyroptotic macrophage-involved immune mechanism, which has important implications for the development of novel strategies to delay senescence and promote reproductive health.

Associations of Blood Absolute Neutrophil Count and Cytokines With Cognitive Function in Dementia-Free Participants: A Population-Based Cohort Study.

BACKGROUND: The relationships of neutrophils and cytokines with cognitive dysfunction are poorly defined. We aimed to investigate the association of peripheral blood absolute neutrophil count (ANC) with cognitive function in older adults and to further explore the mediating role of serum cytokines in this association. METHODS: This population-based cohort study included 1 666 dementia-free participants (age ≥60 years) derived from baseline examinations (March-September 2018) of the Multimodal Intervention to Delay Dementia and Disability in Rural China (MIND-China); of these, 1 087 participants completed follow-up examinations in October-December 2019. We used a neuropsychological test battery to assess episodic memory, verbal fluency, attention, and executive function at the baseline and follow-up examinations. We used Mindray BC-6800 automated hematology analyzer to measure ANC and Meso Scale Discovery to measure serum interleukin-6 (IL-6) and eotaxin-3. RESULTS: The linear regression analysis of cross-sectional data at baseline (n = 1 666) suggested that increased ANC was significantly associated with a lower episodic memory z score (ß coefficient: -0.149, 95% CI: -0.274 to -0.023) and lower long-delayed free recall z score (-0.216, -0.361 to -0.070). Serum IL-6 and eotaxin-3 could mediate 16.16% to 20.21% and 7.55% to 9.35%, respectively, of these associations. The analysis of longitudinal data (n = 1 087) showed a J-shaped relationship of ANC with decline in episodic memory z score (p for nonlinear = .049), and a U-shaped relationship between ANC and decline in long-delayed free recall z score (p for nonlinear = .043). CONCLUSIONS: Increased neutrophils are associated with poor cognitive performance and accelerated decline in episodic memory, and the cross-sectional association is partly mediated by serum cytokines.

Designing salt stress-resilient crops: Current progress and future challenges.

Excess soil salinity affects large regions of land and is a major hindrance to crop production worldwide. Therefore, understanding the molecular mechanisms of plant salt tolerance has scientific importance and practical significance. In recent decades, studies have characterized hundreds of genes associated with plant responses to salt stress in different plant species. These studies have substantially advanced our molecular and genetic understanding of salt tolerance in plants and have introduced an era of molecular design breeding of salt-tolerant crops. This review summarizes our current knowledge of plant salt tolerance, emphasizing advances in elucidating the molecular mechanisms of osmotic stress tolerance, salt-ion transport and compartmentalization, oxidative stress tolerance, alkaline stress tolerance, and the trade-off between growth and salt tolerance. We also examine recent advances in understanding natural variation in the salt tolerance of crops and discuss possible strategies and challenges for designing salt stress-resilient crops. We focus on the model plant Arabidopsis (Arabidopsis thaliana) and the four most-studied crops: rice (Oryza sativa), wheat (Triticum aestivum), maize (Zea mays), and soybean (Glycine max).

Dual-slab Yb:KGd(WO4)2 regenerative amplifier for spectral shaping and high-power output.

A high-power regenerative amplifier (RA) based on dual-slab Yb:KGd(WO4)2 (Yb:KGW) was demonstrated, which provided a maximum average power of 33.7 W at a repetition rate of 75-200 kHz before compression with a central wavelength of 1039 nm, corresponding to an optical-to-optical conversion efficiency of 51.4%. To the best of our knowledge, this is the highest average power from the Yb:KGW solid-state RA. The compressed pulse duration of 205 fs was realized under the maximum output power. By adjusting the gain of the crystals, respectively, the spectral shaping can be achieved. A combination spectrum with root-mean-square (RMS) bandwidth of 4.5 nm was generated with a central wavelength of 1035 nm at an output power of 20 W, the compressed pulse duration was 159 fs. Meanwhile, effective mitigation of thermal effects by dual-slab configuration guaranteed the nearly diffraction-limited beam quality: M x2 = 1.17 and M y2 = 1.20.

Foliar spraying of exogenous uniconazole (S3307) at the flowering stage as an effective method to resist low-temperature stress on mung bean [Vigna radiata (L.) Wilczek].

Low temperature is one of the major constraints on agricultural productivity worldwide and is likely to further increase. Several adaptations and mitigation strategies are required to cope with low-temperature stress. Uniconazole (S3307) could play a significant role in the alleviation of abiotic stress in plants. In this study, the effects of S3307 on the reactive oxygen species (ROS) and antioxidant metabolism were studied in the leaves of mung bean [Vigna radiata (L.) Wilczek]. The experimental results showed that the low-temperature induced accumulation of superoxide anion (O2-) production rate, and malonaldehyde (MDA) contents. Increased proline content and enzymatic antioxidants, including superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD), were found to alleviate oxidative damage under low temperatures. While, S3307 could reduce O2- production rate and MDA contents and increase the activities of SOD, POD, and CAT, slowed the decrease in ascorbic acid (AsA), dehydroascorbic acid (DHA), glutathione (GSH), and oxidized glutathione (GSSG), and promoted increase in soluble sugars (SS), soluble proteins (SP), and proline (Pro) content under low-temperature. At the same time, low temperature leads to lower 100 grain weight and number of grains per plant, which eventually causes yield reduction decreased. Foliar spraying of S3307 could alleviate the yield loss caused by low temperature, and the increase of S3307 treatment was 5.1%-12.5% and 6.3%-32.9% for the two varieties, respectively, compared with CK. In summary, exogenous S3307 pretreatment enhances plant tolerance to low-temperature by improving the antioxidant enzyme activities, increased non-enzymatic antioxidants content, and decreased O2- production rate and MDA contents and inducing alterations in endogenous S3307, and reduce the decrease in mung bean yield.

Development and validation of a multimorbidity risk prediction nomogram among Chinese middle-aged and older adults: a retrospective cohort study.

OBJECTIVES: The aim of this study is to establish a self-simple-to-use nomogram to predict the risk of multimorbidity among middle-aged and older adults. DESIGN: A retrospective cohort study. PARTICIPANTS: We used data from the Chinese Longitudinal Healthy Longevity Survey, including 7735 samples. MAIN OUTCOME MEASURES: Samples' demographic characteristics, modifiable lifestyles and depression were collected. Cox proportional hazard models and nomogram model were used to estimate the risk factors of multimorbidity. RESULTS: A total of 3576 (46.2%) participants have multimorbidity. The result showed that age, female (HR 0.80, 95% CI 0.72 to 0.89), chronic disease (HR 2.59, 95% CI 2.38 to 2.82), sleep time (HR 0.78, 95% CI 0.72 to 0.85), regular physical activity (HR 0.88, 95% CI 0.81 to 0.95), drinking (HR 1.27 95% CI 1.16 to 1.39), smoking (HR 1.40, 95% CI 1.26 to 1.53), body mass index (HR 1.04, 95% CI 1.03 to 1.05) and depression (HR 1.02, 95% CI 1.01 to 1.03) were associated with multimorbidity. The C-index of nomogram models for derivation and validation sets were 0.70 (95% CI 0.69 to 0.71, p=0.006) and 0.71 (95% CI 0.70 to 0.73, p=0.008), respectively. CONCLUSIONS: We have crafted a user-friendly nomogram model for predicting multimorbidity risk among middle-aged and older adults. This model integrates readily available and routinely assessed risk factors, enabling the early identification of high-risk individuals and offering tailored preventive and intervention strategies.

The relationship between servant leadership and nurses' in-role performance: The sequential mediating effects of job autonomy and emotional exhaustion.

AIMS: Drawing on the conservation of resources theory, this study examines the underlying process through which servant leadership is associated with nurses' in-role performance. Specifically, we test the indirect effect of servant leadership on in-role performance via a sequential mediating mechanism of job autonomy and emotional exhaustion. DESIGN: A time-lagged design was implemented using data gathered from two-wave online surveys (1 week apart) of registered nurses from Jiangsu Province, China. METHODS: Between September 2022 and February 2023, we used Wenjuanxing and Credma, which are two powerful and user-friendly data collection platforms, to distribute online surveys to potential participants. We received a total of 220 usable responses and employed the PROCESS Model 4 and Model 6 to assess our proposed hypotheses. RESULTS: Our proposed model was supported. Servant leadership has a positive indirect effect on nurses' in-role performance through job autonomy and emotional exhaustion. Job autonomy has a negative effect on emotional exhaustion. Additionally, job autonomy mediates the negative relationship between servant leadership and emotional exhaustion. CONCLUSION: The present research extends existing nursing studies by unravelling the complex mechanisms underlying the relationship between servant leadership and nurses' in-role performance. Our study also identifies the underlying mechanism of how servant leadership mitigates emotional exhaustion by supporting nurses' job autonomy. IMPACT: The sequential mediation results provide us with a more fine-grained understanding of the relationship between servant leadership and nurses' in-role performance. It further promotes job autonomy and decreases emotional exhaustion, which supports the UN Sustainable Development Goal #3 (Good Health and Well-being). PATIENT OR PUBLIC CONTRIBUTION: This study addresses the UN Sustainable Development Goal #3: 'To ensure healthy lives and promote well-being for all at all ages' and the healthcare providers will benefit from our study. Therefore, the study contributes to a more sustainable organization and society.

Metal-organic framework-based photodynamic combined immunotherapy against the distant development of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive, metastatic and apparently drug-resistant subtype of breast cancer with a higher immune response compared to other types of breast cancer. Photodynamic therapy (PDT) has been gaining popularity for its non-invasive nature, minimal side effects, and spatiotemporally controlled benifits. The use of metal-organic frameworks (MOFs) loaded with programmed death-ligand 1 inhibitors (iPD-L1) offers the possibility of combining PDT with immunotherapy. METHOD: Here, we construct PCN-224, a MOFs with good biocompatibility and biodegradability for the delivery of the PD-L1 small molecule inhibitor BMS-202 to achieve a synergistic anti-tumor strategy of PDT and immunotherapy. Hyaluronic acid (HA) modified PEG (HA-PEG) was synthesized for the outer layer modification of the nanocomplex, which prolongs its systemic circulation time. RESULTS: In vitro cellular experiments show that the nanocomplexes irradiated by 660 nm laser has a strong ability to produce singlet oxygen, which effectively induce PDT. PDT with strong immunogenicity leads to tumor necrosis and apoptosis, and induces immunogenic cell death, which causes tumor cells to release danger associated molecular patterns. In combination with iPD-L1, the combination therapy stimulates dendritic cell maturation, promotes T-cell activation and intratumoral infiltration, and reshapes the tumor immune microenvironment to achieve tumor growth inhibition and anti-distant tumor progression. CONCLUSIONS: MOFs-based nano-systems as a platform for combination therapy offer a potentially effective strategy for the treatment of TNBC with high metastatic rates.

Chronic endometritis incidence in infertile women with and without polycystic ovary syndrome: a propensity score matched study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is known to be associated with chronic low-grade inflammation and endometrial dysfunction. Chronic endometritis (CE) is a type of local inflammation that can contribute to endometrial dysfunction in infertile women. Some clinicians recommend screening for CE in women at high risk, such as those with endometrial polyps. However, it is still uncertain whether there is a relationship between PCOS and CE, as well as whether women with PCOS require enhanced screening for CE. This study was to assess the incidence of CE among infertile women with PCOS by hysteroscopy combined with histopathology CD138 immunohistochemical staining of endometrium. METHODS: A total of 205 patients in the PCOS group and 4021 patients in the non-PCOS group from July 2017 to August 2022 were included in this retrospective study. After nearest-neighbor 1:4 propensity score matching (PSM), 189 PCOS patients were matched with 697 non-PCOS patients. Basic information was recorded. The CE incidence was compared. The risk factors affecting CE incidence were also analyzed. RESULTS: No significantly higher CE incidence in infertile women with PCOS were found either in total analysis or after PSM (P = 0.969; P = 0.697; respectively). Similar results were discovered in the subgroup of Body Mass Index (BMI) (P = 0.301; P = 0.671; P = 0.427; respectively) as well as the four PCOS phenotypes (P = 0.157). Intriguingly, the incidence of CE increased as BMI increased in the PCOS group, even though no significant differences were found (P = 0.263). Multivariate logistic regression showed that age, infertility duration, infertility type, PCOS, and obesity were not the independent risk factors affecting CE incidence. CONCLUSION: The incidence of CE in PCOS patients did not significantly increase compared to non-PCOS patients. Similarly, no significant differences in the incidence of CE were observed among different PCOS phenotypes. The current evidence does not substantiate the need for widespread CE screening among PCOS women, potentially mitigating the undue financial and emotional strain associated with such screenings.

Spatio-temporal characterization of tightly focused femtosecond laser fields formed by paraboloidal mirrors with different F-numbers.

The focusing spatiotemporal property of a femtosecond laser pulse is presented under tight focusing conditions by using the frequency-resolved incident electric field and vector diffraction formulas with the wavefront correction term. In the ideal case, the focused laser intensity reaches its maximum at the F-number of ∼0.35 due to the strong diffraction effect under extremely tight focusing conditions. In spatio-temporal coupling distortion cases, their spatiotemporal Strehl ratios show a trend of improvement as the F-number decreases and this phenomenon is mainly concentrated along the y-direction. Based on the numerical calculation method used in this work, the precise information of tightly focused ultra-intense femtosecond laser fields can be obtained, which is crucial for assessing a focused intensity and describing the motion of charged particles under an extremely strong electric field. Moreover, the evolution law of focal fields with spatiotemporal distortions found in this paper can offer some theoretical guidance for realizing ultrahigh laser intensity in the near future.

A salting-out assisted liquid-liquid extraction method for 25 emerging pesticides in follicular fluid.

Emerging pesticides of neonicotinoids (NEOs) and "Universal Pesticides" (UPs) are a growing global concern due to their growing commercial importance and potential risks to human health. The currently available analytical methods for these pesticides in biomonitoring were usually tailored for limited number of analytes, or were time consuming and costly. In this study, an efficient and sensitive method for the analysis of 16 NEOs and nine UPs in human follicular fluid (FF) was developed by using a salting-out assisted liquid-liquid extraction (SALLE) method and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Method performance was evaluated by calibration linearity (r > 0.99), sensitivity at limits of quantification (0.01-0.50 ng/mL), accuracy at relative recoveries (81-117%) and precision at relative standard deviations (≤16%). The developed method was further validated by analyzing 21 human FF samples that were collected from a hospital in Guangzhou, China. Among the 25 study analytes, two NEOs and six UPs had their detection rates over 85% and medians at 0.048-0.808 ng/mL in the FF samples. Considering the well-known toxicity of these pesticides and their metabolites, it is urgent to figure out exposure profiles of study pesticides and potential reproductive risk for women. To the best of our knowledge, this study is the first to develop and apply the SALLE method in the extraction of 16 NEOs and nine UPs simultaneously in human FF.

417†W, 2.38†mJ Innoslab amplifier compressible to a high pulse quality of 406†fs.

We demonstrate a 417 W, 175 kHz Innoslab chirped pulse amplification laser compressible to short and clean 406 fs pulse duration. A spectral bandwidth (full width at half maximum, FWHM) of ∼3 nm was maintained at full pump power, and the pulses exhibited good pulse quality in a wide tunable pulse energy range from 1.7 mJ to a maximum of 2.38 mJ. At the maximum output power, the compressed pulses were nearly pedestal free. The comprehensive effects of residual high-order dispersion from the front end, the gain shaping effects of the amplifier, and the slight mismatch of third-order dispersion (TOD) between the stretcher (CFBG) and the gating compressor, along with the small nonlinear phase shift accumulated in the amplifier, could have facilitated the high pulse quality. To the best of our knowledge, this is the shortest pulse duration from the Innoslab amplifiers at hundreds of watts average power in the millijoule energy regime.