Efficacy and safety of anti-PD-1/PD-L1-based dual immunotherapies versus PD-1/PD-L1 inhibitor alone in patients with advanced solid tumor: a systematic review and meta-analysis.

INTRODUCTION: Numerous randomized controlled trials (RCTs) have investigated PD-1/PD-L1 inhibitor-based combination therapies. The debate surrounding the potential additive clinical benefits of combination of two immune-oncology (IO) therapies for cancer patients persists. METHODS: Both published and grey sources of randomized clinical trials that compared anti-PD-1/PD-L1-based immunotherapy combinations with monotherapy in patients with advanced or metastatic solid tumors were encompassed. The primary outcome was progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). RESULTS: Our analysis encompassed 31 studies comprising 10,341 patients, which covered 12 distinct immune-oncology combination regimens. Across all patients, the immunotherapy combinations exhibited the capability to enhance the ORR (OR = 1.23 [95% CI 1.13-1.34]) and extend PFS (HR = 0.91 [95% CI 0.87-0.95]). However, the observed enhancement in OS (HR = 0.96 [95% CI 0.91-1.01]) was of no significance. Greater benefits in terms of PFS (HR = 0.82 [95% CI 0.72 to 0.93]) and OS (HR = 0.85 [95% CI 0.73 to 0.99]) may be particularly pronounced in cases where PD-L1 expression is negative. Notably, despite a heightened risk of any-grade TRAEs (OR = 1.72 [95% CI 1.40-2.11]) and grade greater than or equal to 3 TRAEs (OR = 2.01 [95% CI 1.67-2.43]), toxicity was generally manageable. CONCLUSIONS: This study suggests that incorporating an additional immunotherapy agent with PD-1/PD-L1 inhibitors can elevate the response rate and reduce the risk of disease progression, all while maintaining manageable toxicity. However, there remains a challenge in translating these primary clinical benefits into extended overall survival.

The Evolution of C4 Photosynthesis in Flaveria (Asteraceae): Insights from the Flaveria linearis Complex.

Flaveria is a leading model for C4 plant evolution due to the presence of a dozen C3-C4 intermediate species, many of which are associated with a phylogenetic complex centered around Flaveria linearis. To investigate C4 evolution in Flaveria, we updated the Flaveria phylogeny and evaluated gas exchange, starch δ13C, and activity of C4 cycle enzymes in 19 Flaveria species and 28 populations within the F. linearis complex. A principal component analysis identified six functional clusters: (1) C3, (2) sub-C2, (3) full C2, (4) enriched C2, (5) sub-C4, and (6) fully C4 species. The sub-C2 species lacked a functional C4 cycle, while a gradient was present in the C2 clusters from little to modest C4 cycle activity as indicated by δ13C and enzyme activities. Three Yucatan populations of F. linearis had photosynthetic CO2 compensation points equivalent to C4 plants but showed little evidence for an enhanced C4 cycle, indicating they have an optimized C2 pathway that recaptures all photorespired CO2 in the bundle sheath (BS) tissue. All C2 species had enhanced aspartate aminotransferase activity relative to C3 species and most had enhanced alanine aminotransferase activity. These aminotransferases form aspartate and alanine from glutamate and in doing so could help return photorespiratory nitrogen (N) from BS to mesophyll cells, preventing glutamate feedback onto photorespiratory N assimilation. Their use requires upregulation of parts of the C4 metabolic cycle to generate carbon skeletons to sustain N return to the mesophyll, and thus could facilitate the evolution of the full C4 photosynthetic pathway.

Comparative efficacy and safety of COVID-19 vaccines in phase III trials: a network meta-analysis.

BACKGROUND: Over a dozen vaccines are in or have completed phase III trials at an unprecedented speed since the World Health Organization (WHO) declared COVID-19 a pandemic. In this review, we aimed to compare and rank these vaccines indirectly in terms of efficacy and safety using a network meta-analysis. METHODS: We searched Embase, MEDLINE, and the Cochrane Library for phase III randomized controlled trials (RCTs) from their inception to September 30, 2023. Two investigators independently selected articles, extracted data, and assessed the risk of bias. Outcomes included efficacy in preventing symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the incidence of serious adverse events (SAEs) according to vaccine type and individual vaccines in adults and elderly individuals. The risk ratio and mean differences were calculated with 95% confidence intervals using a Bayesian network meta-analysis. RESULTS: A total of 25 RCTs involving 22 vaccines were included in the study. None of vaccines had a higher incidence of SAEs than the placebo. Inactivated virus vaccines might be the safest, with a surface under the cumulative ranking curve (SUCRA) value of 0.16. BIV1-CovIran showed the highest safety index (SUCRA value: 0.13), followed by BBV152, Soberana, Gam-COVID-Vac, and ZF2001. There were no significant differences among the various types of vaccines regarding the efficacy in preventing symptomatic SARS-CoV-2 infection, although there was a trend toward higher efficacy of the mRNA vaccines (SUCRA value: 0.09). BNT162b2 showed the highest efficacy (SUCRA value: 0.02) among the individual vaccines, followed by mRNA-1273, Abdala, Gam-COVID-Vac, and NVX-CoV2373. BNT162b2 had the highest efficacy (SUCRA value: 0.08) in the elderly population, whereas CVnCoV, CoVLP + AS03, and CoronaVac were not significantly different from the placebo. CONCLUSIONS: None of the different types of vaccines were significantly superior in terms of efficacy, while mRNA vaccines were significantly inferior in safety to other types. BNT162b2 had the highest efficacy in preventing symptomatic SARS-CoV-2 infection in adults and the elderly, whereas BIV1-CovIran had the lowest incidence of SAEs in adults.

Family-based genetic analysis in schizophrenia by whole-exome sequence to identify rare pathogenic variants.

Schizophrenia (SCZ) is influenced by a combination of genetic and environmental factors. Although several studies have been conducted to identify the causative loci and genes, few of these loci or genes can be repeated due to the high phenotypic and genetic heterogeneity of disease, and their mechanisms are not fully understood. There may be some "missing heritability" that has not yet been found. In order to investigate the deleterious heritable mutations, whole-exome sequencing (WES) in pedigrees with SCZ was used in the current work. Two unrelated pedigrees with SCZ were recruited to perform WES. Genetic analysis was next performed to find potential variants in accordance with the prioritized strategy. Followed by genetic analysis to detect candidate variants according to the prioritized strategy. Next, a series of algorithms was used to predict the pathogenicity of variants. Sanger sequencing was finally conducted to verify the co-segregation. Recessive mutations in six genes (TFEB, SNAI2, TFAP2B, PRKDC, ST18 in Pedigree 1 and PKHD1L1 in Pedigree 2) that co-segregated with SCZ in two families were discovered through genetic analysis by WES. Sanger sequencing verified that all of the mutations in the affected siblings were homozygous. These results corroborated the hypothesis that SCZ exhibits strong heterogeneity and complex inheritance patterns. The newly discovered homozygous variations deepen our understanding of the mutation spectrum and offer more proof for the involvement of TFEB, SNAI2, TFAP2B, PRKDC, ST18, and PKHD1L1 in the development of SCZ.

Destructive interference in N2+ lasing.

We report an unexpected experimental observation in rotation-resolved N2+ lasing that the R-branch lasing intensity from a single rotational state in the vicinity of 391 nm can be greatly stronger than the P-branch lasing intensity summing over the total rotational states at suitable pressures. According to a combined measurement of the dependence of the rotation-resolved lasing intensity on the pump-probe delay and the rotation-resolved polarization, we speculate that the destructive interference can be induced for the spectrally-indistinguishable P-branch lasing due to the propagation effect while the R-branch lasing is little affected due to its discrete spectral property, after precluding the role of rotational coherence. These findings shed light on the air-lasing physics, and provide a feasible route to manipulate air lasing intensity.

Ectopic Expression of the Transcriptional Regulator silky3 Causes Pleiotropic Meristem and Sex Determination Defects in Maize Inflorescences.

Maize (Zea mays) is a monoecious plant, in which inflorescence morphogenesis involves complicated molecular regulatory mechanisms. Although many related genes have been cloned, our understanding of the molecular mechanism underlying maize inflorescence development remains limited. Here, we identified a maize semi-dominant mutant Silky3 (Si3), which displays pleiotropic defects during inflorescence development, including loss of determinacy and identity in meristems and floral organs, as well as the sexual transformation of tassel florets. We cloned the si3 gene using a map-based approach. Functional analysis reveals that SI3 is a nuclear protein and may act as a transcriptional regulator. Transcriptome analysis reveals that the ectopic expression of si3 strongly represses multiple biological processes, especially the flower development pathways. RNA in situ hybridization similarly shows that the expression patterns of genes responsible for flower development are changed in the Si3 mutant. In addition, the homeostasis of jasmonic acid and gibberellic acid are altered in the Si3 young tassels, and application of exogenous jasmonic acid can rescue the sex reversal phenotype of Si3 The defects we characterized in various regulatory pathways can explain the complex phenotypes of Si3 mutant, and this study deepens our knowledge of maize inflorescence development.

Neoadjuvant alectinib in locally advanced lung adenocarcinoma with anaplastic lymphoma kinase rearrangement: case series and literature review.

In view of the success of targeted therapy in the field of advanced lung cancer, it is gradually pushed further to neoadjuvant therapy. Alectinib has been recommended for advanced anaplastic lymphoma kinase (ALK) + non-small cell lung cancer (NSCLC) in first-line therapy. Here, we report two cases of neoadjuvant alectinib in locally advanced lung adenocarcinoma with ALK rearrangement. Case 1 was a 64-year-old man with no history of smoking who was diagnosed with the clinical stage as IIIB, with ALK fusion-positive. Chest-enhanced computed tomography (CT) revealed marked regression and achieved partial response (PR) incorporated with grade 3 interstitial pneumonia after 44 days of alectinib neoadjuvant therapy. Interstitial pneumonia improved after methylprednisolone therapy, then thoracoscopic lobe resection with lymph node dissection was performed with blood loss. The pathological assessment was a pathologic complete response(pCR). Case 2 was a 66-year-old man who had a routine physical examination and then diagnosed with a clinical-stage IIIB by CT-guided percutaneous cutting needle biopsy (PCNB). Chemotherapy with 1 cycle of pemetrexed combined with nedaplatin was performed in the interval waiting for next-generation sequencing (NGS) results. NGS testing revealed an EML4-ALK fusion mutation. After 109 days of alectinib treatment, radiographic evaluation was classified as PR and then he underwent thoracoscopic upper lobectomy smoothly with pathological assessment as a major pathological response (MPR). To date, neoadjuvant alectinib has only been reported in a few cases in locally advanced lung adenocarcinoma with ALK-rearranged. Neoadjuvant alectinib may be feasible in locally advanced disease for complete resection. The duration and safety of neoadjuvant therapy with alectinib still need further study.

Long Non Coding RNA FOXD3­AS1 Alleviates Allergic Rhinitis by Elevating the Th1/Th2 Ratio via the Regulation of Dendritic Cells.

This article aimed to explore whether the regulation of Th1/Th2 immune responses by FOXD3-AS1 is associated with dendritic cells (DCs) in allergic rhinitis (AR). HE staining was performed to assess the pathological changes in the nasal mucosa; ELISA was performed to measure the levels of Th1/Th2-related cytokines; flow cytometry was performed to analyze Th1/Th2 cells and MHC-II-, CD80-, and CD86-positive DCs; and qRT‒PCR and western blotting were performed to measure mRNA and protein expression levels, respectively. Our data revealed that LV-FOXD3-AS1 improved AR and increased the Th1/Th2 cell ratio in AR model mice. LV-FOXD3-AS1 further inhibited DC maturation both in vivo and in vitro. Moreover, the coculture system of DCs and CD4+ T cells demonstrated that LV-FOXD3-AS1 increased the Th1/Th2 cell ratio by inhibiting the maturation of DCs. In addition, LV-FOXD3-AS1 reduced the level of phosphorylated STAT6 in DCs derived from healthy mice, and STAT6 overexpression eliminated the inhibitory effect of LV-FOXD3-AS1 on the maturation of DCs. In summary, LV-FOXD3-AS1 ameliorated AR by increasing the Th1/Th2 cell ratio by inhibiting DC maturation via the inhibition of STAT6 phosphorylation. Our data confirmed the protective effect of FOXD3-AS1 in AR and provided a novel idea for the treatment of this disease.

Neuroimaging markers of early neurological deterioration in acute isolated pontine infarction.

BACKGROUND: Imaging indicators of early neurological deterioration (END) in patients with acute isolated pontine infarctions (AIPI) remained ambiguous. We aimed to find more specific neuroimaging markers for the development of END in patients with AIPI. METHODS: Patients with AIPI within 72 h of stroke onset were screened from a stroke database from January 2018 to July 2021 in the First Affiliated Hospital of Zhengzhou University. Clinical characteristics, laboratory tests, and imaging parameters were collected. The layers having the largest infarct area on diffusion-weighted imaging (DWI) and T2 sequences were chosen. On the transverse plane of DWI and sagittal plane of T2-Flair images, the maximum length (a, m) and maximum width (b, n) vertical to the length of the infarcted lesions were measured respectively. On the sagittal plane of T2-Flair image, the maximum ventrodorsal length (f) and rostrocaudal thickness (h) were measured. On the sagittal plane, lesions were evenly split into upper, middle, and lower types based on the lesion's location in the pons. The ventral and dorsal types of location were separated based on whether the ventral borders of the pons were involved on transvers plane. END was defined as a ≥2 point increase in the National Institutes of Health Stroke Scale (NIHSS) total score or a ≥1 point increase in the motor items within 72 h after admission. Multivariate logistic regression analyses were used to explore risk factors associated with END. The receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) was performed to estimate the discriminative power and determine the optimal cut-off points of imaging parameters on the prediction of END. RESULTS: A total of 218 patients with AIPI were included in the final analysis. END occurred in 61 cases (28.0%). Multivariate logistic regression analysis showed that the ventral type of lesion location was associated with END in all models adjusted. In addition, in Model 1, b (odds ratio (OR) 1.145, 95% confidence interval (95% CI), 1.007-1.301) and n (OR 1.163, 95% CI 1.012-1.336); in Model 2, b*n (OR 1.010, 95% CI 1.002-1.018); in Model 3, n (OR 1.179, 95% CI, 1.028-1.353); and in Model 4, b (OR 1.143, 95% CI 1.006-1.298) and n (OR 1.167, 95% CI 1.016-1.341) were found to be associated with END respectively after different adjustments. ROC curve analysis with END showed that the AUC, the optimal cut-off value, and its sensitivity and specificity were 0.743 (0.671-0.815), 9.850 mm, and 68.9% and 79.0% for b; 0.724 (0.648-0.801), 10.800 mm, and 57.4% and 80.9% for n; and 0.772 (0.701-0.842), 108.274 mm2, and 62.3% and 85.4% for b*n, respectively (b*n vs b: P =0.213; b*n vs n: P =0.037; b vs n: P =0.645). CONCLUSIONS: Our study revealed that besides the ventral type of lesion location, the maximum width of lesion on the transverse plane of DWI and sagittal plane of T2 image (b, n) may be imaging markers for the development of END in AIPI patients, and the product of the two (b*n) showed a better prediction value on the risks of END.

Single-Cell Chromatin and Gene-Regulatory Dynamics of Mouse Nephron Progenitors.

BACKGROUND: We reasoned that unraveling the dynamic changes in accessibility of genomic regulatory elements and gene expression at single-cell resolution will inform the basic mechanisms of nephrogenesis. METHODS: We performed single-cell ATAC-seq and RNA-seq both individually (singleomes; Six2GFP cells) and jointly in the same cells (multiomes; kidneys) to generate integrated chromatin and transcriptional maps in mouse embryonic and neonatal nephron progenitor cells. RESULTS: We demonstrate that singleomes and multiomes are comparable in assigning most cell states, identification of new cell type markers, and defining the transcription factors driving cell identity. However, multiomes are more precise in defining the progenitor population. Multiomes identified a "pioneer" bHLH/Fox motif signature in nephron progenitor cells. Moreover, we identified a subset of Fox factors exhibiting high chromatin activity in podocytes. One of these Fox factors, Foxp1, is important for nephrogenesis. Key nephrogenic factors are distinguished by strong correlation between linked gene regulatory elements and gene expression. CONCLUSION: Mapping the regulatory landscape at single-cell resolution informs the regulatory hierarchy of nephrogenesis. Paired single-cell epigenomes and transcriptomes of nephron progenitors should provide a foundation to understand prenatal programming, regeneration after injury, and ex vivo nephrogenesis.

Identification and validation of ferroptosis-related genes for chronic rhinosinusitis with nasal polyps.

PURPOSE: Even though the great progress in the field of chronic rhinosinusitis with nasal polyps (CRSwNP) has been achieved, ferroptosis and its molecular mechanism in CRSwNP remain blank. We are the first to study the relationship between CRSwNP and ferroptosis, aiming to identify ferroptosis-related genes in the process of CRSwNP. METHODS: Using the GEO database and the FerrDb database, significantly differentially expressed ferroptosis-related genes (DEFGs) were selected between CRSwNP-NP and CRSwNP-IT specimens. Then, the protein-protein interaction (PPI) network of ferroptosis-related genes was constructed. Functional enrichment analyses (GSVA, GO, KEGG, and GeneCodis analyses) were introduced in our study. Besides, based on the GSE136825 data set, DEFGs between CRSwNP-NP and CS-IT specimens were also analyzed. Finally, qRT-PCR was performed to validate the selected ferroptosis-related genes with clinical samples. RESULTS: 31 significantly DEFGs were identified between CRSwNP-NP and CRSwNP-IT specimens. Functional enrichment analyses and the analysis of GeneCodis 4 pointed out that DEFGs may potentially be involved in some related KEGG pathways. 8 DEFGs were selected between CRSwNP-NP and CS-IT specimens. The experimental verification indicated that 4 genes (GPX2, CDO1, CAV1, and TP53) were the important DEFGs of CRSwNP. The Venn diagrams proved that CDO1 and GPX2 were considered as the most important DEFGs genes of CRSwNP, especially GPX2. CONCLUSIONS: Though a comprehensive bioinformatics analysis and the experimental verification, CDO1 and GPX2 were considered as the important ferroptosis-related genes of CRSwNP, especially GPX2. However, further molecular biological experiments would be still required to uncover the underlying mechanism between ferroptosis and CRSwNP.

Identification of Side Chain Oxidized Sterols as Novel Liver X Receptor Agonists with Therapeutic Potential in the Treatment of Cardiovascular and Neurodegenerative Diseases.

The nuclear receptors-liver X receptors (LXR α and ß) are potential therapeutic targets in cardiovascular and neurodegenerative diseases because of their key role in the regulation of lipid homeostasis and inflammatory processes. Specific oxy(phyto)sterols differentially modulate the transcriptional activity of LXRs providing opportunities to develop compounds with improved therapeutic characteristics. We isolated oxyphytosterols from Sargassum fusiforme and synthesized sidechain oxidized sterol derivatives. Five 24-oxidized sterols demonstrated a high potency for LXRα/ß activation in luciferase reporter assays and induction of LXR-target genes APOE, ABCA1 and ABCG1 involved in cellular cholesterol turnover in cultured cells: methyl 3ß-hydroxychol-5-en-24-oate (S1), methyl (3ß)-3-aldehydeoxychol-5-en-24-oate (S2), 24-ketocholesterol (S6), (3ß,22E)-3-hydroxycholesta-5,22-dien-24-one (N10) and fucosterol-24,28 epoxide (N12). These compounds induced SREBF1 but not SREBP1c-mediated lipogenic genes such as SCD1, ACACA and FASN in HepG2 cells or astrocytoma cells. Moreover, S2 and S6 enhanced cholesterol efflux from HepG2 cells. All five oxysterols induced production of the endogenous LXR agonists 24(S)-hydroxycholesterol by upregulating the CYP46A1, encoding the enzyme converting cholesterol into 24(S)-hydroxycholesterol; S1 and S6 may also act via the upregulation of desmosterol production. Thus, we identified five novel LXR-activating 24-oxidized sterols with a potential for therapeutic applications in neurodegenerative and cardiovascular diseases.

Antibacterial-Anti-Inflammatory-Bone Restoration Procedure Achieved by MIN-Loaded PLGA Microsphere for Efficient Treatment of Periodontitis.

The main development process of periodontitis involves periodontal pathogenic bacteria as the initiating factor causing the onset of destructive inflammation, which in turn stimulates the destruction of periodontal tissue. It is difficult to achieve the eradication of periodontitis due to the complex interaction among antibacterial, anti-inflammatory, and bone restoration. Herein, we propose an antibacterial-anti-inflammatory-bone restoration procedural treatment strategy with minocycline (MIN) for the efficient treatment of periodontitis. In brief, MIN was prepared into PLGA microspheres with tunable release behavior using different species of PLGA, respectively. The optimally selected PLGA microspheres (LA:GA with 50:50, 10 kDa, and carboxyl group) had a drug loading of 16.91%, an in vitro release of approximately 30 days, which also had a particle size of approximately 11.8 µm with a smooth appearance and a rounded morphology. The DSC and XRD results showed that the MIN was completely encapsulated in the microspheres as an amorphous state. Cytotoxicity tests demonstrated the safety and biocompatibility of the microspheres (cell viabilities at a concentration of 1-200 µg/mL were greater than 97%), and in vitro bacterial inhibition tests showed that the selected microspheres could achieve effective bacterial inhibition at the initial stage after administration. The favorable anti-inflammatory (low TNF-α and IL-10 levels) and bone restoration effects (BV/TV: 71.8869%; BMD: 0.9782 g/cm3; TB.Th: 0.1366 mm; Tb.N: 6.9318 mm-1; Tb.Sp: 0.0735 mm) were achieved in a SD rat periodontitis model after administering once a week for four weeks. The MIN-loaded PLGA microspheres were proved to be an efficient and safe treatment for periodontitis by procedural antibacterial, anti-inflammatory, and bone restoration.

An Artificial Intelligence Approach for Tackling Conformational Energy Uncertainties in Chiroptical Spectroscopies.

Determination of the absolute configuration of chiral molecules is a prerequisite for obtaining a fundamental understanding in any chirality-related field. The interaction with polarised light has proven to be a powerful means to determine this absolute configuration, but its application rests on the comparison between experimental and computed spectra for which the inherent uncertainty in conformational Boltzmann factors has proven to be extremely hard to tackle. Here we present a novel approach that overcomes this issue by combining a genetic algorithm that identifies the relevant conformers by accounting for the uncertainties in DFT relative energies, and a hierarchical clustering algorithm that analyses the trends in the spectra of the considered conformers and identifies on-the-fly when a given chiroptical technique is not able to make reliable predictions. The effectiveness of this approach is demonstrated by considering the challenging cases of papuamine and haliclonadiamine, two bis-indane natural products with eight chiral centres and considerable conformational heterogeneity that could not be assigned unambiguously with current approaches.

Host stimulator of interferon genes is essential for the efficacy of anti-programmed cell death protein 1 inhibitors in non-small cell lung cancer.

The stimulator of interferon genes (STING) pathway is important for anticancer immune responses. However, the relative contributions of host and tumour STING in anti-programmed cell death protein 1 (anti-PD-1) inhibitor responses in non-small cell lung cancer (NSCLC) are unknown. STING expression in tumour and blood was associated with anti-PD-1 therapy in NSCLC patients; Moreover, loss of PD-1 inhibitor therapeutic potency was demonstrated in STING KO (knock out) splenocytes and STING KO mice. STING knock-down in tumour cells had no effect. STING on CD8+ T cells and host cells, not tumour cells, correlated with clinical effect of anti-PD-1 therapy in NSCLC patients. Finally, adoptive transfer of CD8+ T cells restored PD-1 inhibitor anticancer effects. STING in host cells but not in tumour cells mediates anti-PD-1 inhibitor responses in cancer immunotherapy and could be used to select advantageous NSCLC patients from immunotherapy.

Immune checkpoint inhibitors alone vs immune checkpoint inhibitors-combined chemotherapy for NSCLC patients with high PD-L1 expression: a network meta-analysis.

BACKGROUND: We indirectly compared the effects of immune checkpoint inhibitors alone (ICI) and ICI-combined chemotherapy (chemo-ICI) in patients with non-small cell lung cancer who had high programmed death-ligand 1 (PD-L1) expression (defined as tumour proportion score ≥50% or TC3/IC3) through network meta-analyses. METHODS: Through literature searches, we shortlisted 22 randomised controlled trials encompassing 4289 patients, with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) set as the primary outcomes. The dichotomous data for ORR and hazard ratios (HRs) and their 95% confidence intervals (CIs) for OS and PFS were extracted. RESULTS: We found that chemo-ICI had significantly improved ORR (OR 1.7, 95% CI 1.1-2.5) and PFS (HR 0.59, 95% CI: 0.48-0.74) relative to ICI. Although no significant difference in OS was observed, the analyses revealed that the chemo-ICI patients tended to undergo fewer progression events than ICI patients (HR 0.82, 95% CI 0.6-1.1). In subgroup analysis, the non-squamous, PD-1 inhibitor and first-line treatment cohorts exhibited significant differences in ORR and PFS, but not in OS. However, in the squamous, PD-L1 inhibitor, and previously treated cohorts, PFS, OS and ORR were not different between chemo-ICI and ICI patients. CONCLUSIONS: In conclusion, for non-squamous NSCLC patients, accepting PD-1 as the first-line treatment may be a relatively better option.

Comparison between immunotherapy efficacy in early non-small cell lung cancer and advanced non-small cell lung cancer: a systematic review.

BACKGROUND: Currently, immunotherapy is widely used in the treatment of various stages of non-small cell lung cancer. According to clinical experience and results of previous studies, immunotherapy as neoadjuvant therapy seems to exhibit better efficacy against early resectable non-small cell lung cancer as compared to advanced lung cancer, which is often defined as unresectable non-small cell lung cancer. However, this observation has not been established in clinical studies. This systematic review aimed to evaluate the efficacy of immunotherapy in early and late lung cancer, wherein objective response rate (ORR) and disease control rate (DCR) were used as evaluation indexes. The present study also evaluated the safety of immunotherapy in early and late lung cancer, wherein the rate of treatment-related adverse reactions (TRAEs) was used as an indicator. METHODS: Electronica databases, including PubMed, Cochrane Library, Embase, and other databases, were searched to identify relevant studies. Besides this, all the available reviews, abstracts, and meeting reports from the main international lung cancer meetings were searched manually. ORR, DCR, and TRAEs were extracted as the primary outcomes. RESULTS: A total of 52 randomized controlled trials involving 13,660 patients were shortlisted. It was observed that immunotherapy alone significantly improved DCR in early lung cancer in comparison to advanced lung cancer. Importantly, the improvement in ORR was not to the same extent as reported in the case of advanced lung cancer. The combination of immunotherapy with other therapies, especially immunochemotherapy, significantly improved ORR and DCR in early lung cancer. In terms of safety, immunotherapy either alone or in combination with other therapies exhibited a better safety profile in early lung cancer than in advanced lung cancer. CONCLUSIONS: Altogether, the benefits of immunotherapy in early lung cancer appeared to be better than those observed in advanced lung cancer, especially with the regard to the regimen of immunotherapy in combination with chemotherapy. In terms of safety, both immunotherapy alone and its combination with chemotherapy were found to be safer in early lung cancer as compared to advanced lung cancer.

Maize cytosolic invertase INVAN6 ensures faithful meiotic progression under heat stress.

Faithful meiotic progression ensures the generation of viable gametes. Studies suggested the male meiosis of plants is sensitive to ambient temperature, but the underlying molecular mechanisms remain elusive. Here, we characterized a maize (Zea mays ssp. mays L.) dominant male sterile mutant Mei025, in which the meiotic process of pollen mother cells (PMCs) was arrested after pachytene. An Asp-to-Asn replacement at position 276 of INVERTASE ALKALINE NEUTRAL 6 (INVAN6), a cytosolic invertase (CIN) that predominantly exists in PMCs and specifically hydrolyses sucrose, was revealed to cause meiotic defects in Mei025. INVAN6 interacts with itself as well as with four other CINs and seven 14-3-3 proteins. Although INVAN6Mei025 , the variant of INVAN6 found in Mei025, lacks hydrolytic activity entirely, its presence is deleterious to male meiosis, possibly in a dominant negative repression manner through interacting with its partner proteins. Notably, heat stress aggravated meiotic defects in invan6 null mutant. Further transcriptome data suggest INVAN6 has a fundamental role for sugar homeostasis and stress tolerance of male meiocytes. In summary, this work uncovered the function of maize CIN in male meiosis and revealed the role of CIN-mediated sugar metabolism and signalling in meiotic progression under heat stress.

Genetically predicted frailty index and risk of stroke and Alzheimer's disease.

BACKGROUND AND PURPOSE: Previous studies have reported the association between frailty and stroke or Alzheimer's disease (AD). However, the causality remains unclear. The aim of the present study was to evaluate whether genetically predicted frailty is associated with the risk of stroke or AD by a Mendelian randomization (MR) study. METHODS: Genetic variants associated with the frailty index (FI) were obtained from a large genome-wide association study (GWAS). Summary-level data for stroke and AD were adopted from the corresponding large GWAS of individuals of European ancestry. The inverse variance weighted method was used for estimating causal effects. Multivariable analysis was performed for further adjustment. RESULTS: The present MR study indicated a suggestive association between genetically predicted FI and a higher risk of any stroke (odds ratio 1.360, 95% confidence interval 1.006-1.838, p = 0.046). Regarding the subtypes of stroke, genetically predicted FI was associated with a higher risk of large artery atherosclerosis stroke (LAS) (odds ratio 2.487, 95% confidence interval 1.282-4.826, p = 0.007). No causal links were identified between genetically predicted FI and any ischaemic stroke, intracranial haemorrhage, cardioembolic stroke, small artery stroke, AD or AD-by-proxy. Multivariable MR analysis indicated that the association of genetically predicted FI with LAS was attenuated after adjustment for inflammatory bowel disease (p = 0.114). CONCLUSIONS: The MR study suggested that genetically predicted FI may be associated with an increased risk of any stroke. Subgroup analysis indicated a suggestive association between genetically predicted FI and the risk of LAS. The underlying mechanisms need further investigation.

Coherent-interface-induced second hardening deformation of Al-Mg-Al nanolayers by molecular dynamics simulations.

Thermal diffusion plays an important role in the determination of the structures and properties of interfaces and nanolayers. Here we report results from molecular dynamics simulations of the tensile behavior of Al-Mg-Al nanolayers with their Al/Mg interfaces being joined by the thermal diffusion of atoms. We find that a different deformation mechanism applies in each case: low thermal diffusion temperatures (300 ≤ T1 < 664 K) and high thermal diffusion temperatures (664 ≤ T1 ≤ 846 K). The formation of coherent Al/Mg interfaces in the case of high T1 induces the second hardening deformation of Al-Mg-Al nanolayers before the stress reaching the tensile strength, significantly enhancing the tensile properties of Al-Mg-Al nanolayers in comparison to the case of low T1. This difference would provide guidance on the improvement of the mechanical properties of Al-Mg layered systems.