Presentation_1_Efficacy and safety of brigatinib in ALK-positive non-small cell lung cancer treatment: A systematic review and meta-analysis.pdf

BackgroundBrigatinib is a central nervous system-active second-generation anaplastic lymphoma kinase (ALK) inhibitor that targets a broad range of ALK rearrangements in patients with non-small cell lung cancer (NSCLC). The current study aimed to analyze the pooled effects and adverse events of brigatinib in patients with ALK-positive NSCLC.MethodsThe pooled estimates and 95% confidence intervals (CI) were calculated with DerSimonian-Laird method and the random effect model.ResultsThe pooled objective response rate (ORR) and disease control rate (DCR) of brigatinib were 64% (95% CI 45%-83%) and 88% (95% CI 80%-96%), respectively. The pooled mPFS was 10.52 months (95% CI 7.66-13.37). In the subgroup analyses by treatment line, the highest mPFS was reached in first-line treatment (24.00 months, 95% CI 18.40-43.20), followed by post-crizotinib second-line treatment (mPFS=16.26 months, 95% CI 12.87-19.65), and second-line with any prior ALK tyrosine kinase inhibitors (mPFS=12.96 months, 95% CI 11.14-14.78). Among patients with any baseline brain metastases, the pooled intracranial ORR (iORR) was estimated as 54% (95% CI 35%-73%) for any treatment line, and 60% (95% CI 39%-81%) for first-line treatment. Intracranial PFS (iPFS) reached 19.26 months (95% CI 14.82-23.70) in patients with any baseline brain metastases. Creatine phosphokinase (CPK) increased (44%, 95% CI 26%-63%), diarrhea (37%, 95% CI 27%-48%), and nausea (28%, 95% CI 17%-39%) of any grade were the most common adverse events.ConclusionBrigatinib is effective in the treatment of patients with ALK-positive NSCLC, particularly showing robust intracranial PFS. Brigatinib used as first-line treatment yielded superior PFS compared with brigatinib used as other treatment lines. These results suggested a benefit of using brigatinib earlier in the patient’s management. All adverse events are manageable, with CPK increased and gastrointestinal reactions found to be the most common types.Systematic Review Registrationhttps://inplasy.com/inplasy-2022-3-0142/, identifier (INPLASY202230141).</p

DataSheet_1_Efficacy and safety of brigatinib in ALK-positive non-small cell lung cancer treatment: A systematic review and meta-analysis.pdf

BackgroundBrigatinib is a central nervous system-active second-generation anaplastic lymphoma kinase (ALK) inhibitor that targets a broad range of ALK rearrangements in patients with non-small cell lung cancer (NSCLC). The current study aimed to analyze the pooled effects and adverse events of brigatinib in patients with ALK-positive NSCLC.MethodsThe pooled estimates and 95% confidence intervals (CI) were calculated with DerSimonian-Laird method and the random effect model.ResultsThe pooled objective response rate (ORR) and disease control rate (DCR) of brigatinib were 64% (95% CI 45%-83%) and 88% (95% CI 80%-96%), respectively. The pooled mPFS was 10.52 months (95% CI 7.66-13.37). In the subgroup analyses by treatment line, the highest mPFS was reached in first-line treatment (24.00 months, 95% CI 18.40-43.20), followed by post-crizotinib second-line treatment (mPFS=16.26 months, 95% CI 12.87-19.65), and second-line with any prior ALK tyrosine kinase inhibitors (mPFS=12.96 months, 95% CI 11.14-14.78). Among patients with any baseline brain metastases, the pooled intracranial ORR (iORR) was estimated as 54% (95% CI 35%-73%) for any treatment line, and 60% (95% CI 39%-81%) for first-line treatment. Intracranial PFS (iPFS) reached 19.26 months (95% CI 14.82-23.70) in patients with any baseline brain metastases. Creatine phosphokinase (CPK) increased (44%, 95% CI 26%-63%), diarrhea (37%, 95% CI 27%-48%), and nausea (28%, 95% CI 17%-39%) of any grade were the most common adverse events.ConclusionBrigatinib is effective in the treatment of patients with ALK-positive NSCLC, particularly showing robust intracranial PFS. Brigatinib used as first-line treatment yielded superior PFS compared with brigatinib used as other treatment lines. These results suggested a benefit of using brigatinib earlier in the patient’s management. All adverse events are manageable, with CPK increased and gastrointestinal reactions found to be the most common types.Systematic Review Registrationhttps://inplasy.com/inplasy-2022-3-0142/, identifier (INPLASY202230141).</p

Volatility of Cl-Initiated C₁₂–C₁₄ <i>n</i>‑Alkylcyclohexane Secondary Organic Aerosol: Effects of NO_<i>x</i> and Photoaging

Long-chain alkanes are important components of intermediate-volatility organic compounds, especially for C12–C14 cyclic compounds. In this study, we focus on the volatilities of C12–C14 n-alkylcyclohexane secondary organic aerosol (SOA) initiated by Cl atoms and investigate the influence of NOx, aging time, precursors, and SOA mass loading. Dilution and precursors seem to have little effect on the SOA volatility. Low-volatility organic compounds (LVOCs) account for a dominant part of SOA volatility distribution. Due to the presence of NOx, more fractions of extremely low-volatility OCs (ELVOCs) and a higher carbon oxidation state (OS̅C) result in a decrease in the SOA volatility. During the aging period, the fraction of ELVOCs increased, and semi-volatile organic compounds (SVOCs) decreased simultaneously. Even after 9 h of photoaging, the particle fractions of ELVOCs exceeded those of SVOCs to be the second largest part following LVOCs under high-NOx conditions. The particle-phase oligomerization is the dominant way that influenced the SOA volatility during the photoaging period, according to the product analysis. This study emphasizes the importance of Cl-initiated alkane SOA in the polluted region with high NOx levels

The temporal and spatial pattern of <i>smyd1a</i> expression in zebrafish embryos.

<p><b>A.</b> RT-PCR results show temporal expression of <i>smyd1a</i> in zebrafish embryos from fertilization to day 5. <i>Elongation factor 1-alpha (ef-1α)</i> was used as control. <b>B.</b> RT-PCR analysis shows the alternative splicing of <i>smyd1b</i> exon 5 generating two isoforms of <i>smyd1b</i>, <i>smyd1b</i>_tv1 and <i>smyd1b</i>_tv2. <b>C.</b> RT-PCR analysis shows the lack of alternative splicing of exon 5 in <i>smyd1a</i> in zebrafish embryos. <b>D–I.</b> Whole mount in situ hybridization shows the spatial pattern of <i>smyd1a</i> mRNA expression using a dig-labeled antisense probe. <i>smyd1a</i> expression was detected in skeletal muscles of zebrafish embryos at 24 (D, E, F) and 48 (G, H. I) hpf. D, G represent the side view; E, H repre4sent the dorsal view; F, I represent the cross sections.</p

Expression and Functional Characterization of Smyd1a in Myofibril Organization of Skeletal Muscles

<div><p>Background</p><p>Smyd1, the founding member of the Smyd family including Smyd-1, 2, 3, 4 and 5, is a SET and MYND domain containing protein that plays a key role in myofibril assembly in skeletal and cardiac muscles. Bioinformatic analysis revealed that zebrafish genome contains two highly related <i>smyd1</i> genes, <i>smyd1a</i> and <i>smyd1b</i>. Although Smyd1b function is well characterized in skeletal and cardiac muscles, the function of Smyd1a is, however, unknown.</p><p>Methodology/Principal Findings</p><p>To investigate the function of Smyd1a in muscle development, we isolated <i>smyd1a</i> from zebrafish, and characterized its expression and function during muscle development via gene knockdown and transgenic expression approaches. The results showed that <i>smyd1a</i> was strongly expressed in skeletal muscles of zebrafish embryos. Functional analysis revealed that knockdown of <i>smyd1a</i> alone had no significant effect on myofibril assembly in zebrafish skeletal muscles. However, knockdown of <i>smyd1a</i> and <i>smyd1b</i> together resulted in a complete disruption of myofibril organization in skeletal muscles, a phenotype stronger than knockdown of <i>smyd1a</i> or <i>smyd1b</i> alone. Moreover, ectopic expression of zebrafish <i>smyd1a</i> or mouse <i>Smyd1</i> transgene could rescue the myofibril defects from the <i>smyd1b</i> knockdown in zebrafish embryos.</p><p>Conclusion/Significance</p><p>Collectively, these data indicate that Smyd1a and Smyd1b share similar biological activity in myofibril assembly in zebrafish embryos. However, Smyd1b appears to play a major role in this process.</p></div

The myofibril defects from <i>smyd1b</i> knockdown could be rescued by ectopic expression of zebrafish <i>smyd1a</i> or mouse Smyd1.

<p>The <i>smyd1b</i> ATG-MO was co-injected with <i>smyd1b:zfsmyd1a^myc</i> or <i>smyd1b:mSmyd1^myc</i> transgene into zebrafish embryos at 1 or 2 cells stages. Myosin thick filament organization and transgene expression were analyzed by double immunostaining with anti-MHC (F59, green) and anti-myc (9E10, red) antibodies. <b>A, C, E.</b> Double immunostaining with anti-MHC (A) and anti-myc (C) antibodies shows the normal thick filament organization in myofibers expressing the myc-tagged zebrafish <i>smyd1a</i> transgene at 24 hpf. E, merged picture of <b>A</b> and <b>C. B, D, F.</b> Double immunostaining with anti-MHC (B) and anti-myc (D) antibodies shows the normal thick filament organization in myofibers expressing the myc-tagged mouse Smyd1 transgene at 24 hpf. F, merged picture of B with D. D and F showed the sarcomeric localization of myc-tagged mouse Smyd1 (red). The myc-tagged mouse Smyd1 was localized in the middle of the MHC thick filament (F), a region normally occupied by the M-line. Scale bars: 20 µm in E; 14 µm in F.</p

The effect of <i>smyd1a</i> or <i>smyd1b</i> single or double knockdown on the Z-line organization in skeletal muscles.

<p>Zebrafish embryos injected with <i>smyd1b</i> MO or <i>smyd1a</i> MO or both were fixed at 28, 48 and 72 hpf. Z-line organization was analyzed by immunostaining with anti-α-actinin antibody (EA-53), and followed by FTIC-labeled secondary antibody. The images represent side view of trunk muscles around segment 10. <b>A–C.</b> Lateral view of Z-line organization in skeletal muscle fibers of control-MO injected embryos at 28 (A), 48 (B) and 72 (C) hpf. <b>D–F.</b> Lateral view of Z-line organization in skeletal muscle fibers of <i>smyd1a</i> E8I8-MO injected embryos at 28 (D), 48 (E) and 72 (F) hpf. <b>G–I.</b> Lateral view of Z-line organization in skeletal muscle fibers of <i>smyd1a</i> E8I8-MO and E9I9-MO co-injected embryos at 28 (G), 48 (H) and 72 (I) hpf. <b>J–L.</b> Lateral view of Z-line organization in skeletal muscle fibers of <i>smyd1b</i> ATG-MO injected embryos at 28 (J), 48 (K) and 72 (L) hpf. <b>M–O.</b> Lateral view of Z-line organization in skeletal muscle fibers of <i>smyd1a</i> E8I8-MO and <i>smyd1b</i> ATG-MO co-injected embryos at 28 (M), 48 (N) and 72 (O) hpf. Scale bars: 20 µm in A–C.</p

BTS inhibits skeletal muscle contraction and suppresses thick and thin filament assembly in skeletal muscles of zebrafish embryos.

<p>A–D. Morphological comparison of control (A, B) or BTS-treated (C, D) embryos at 48 hpf (A, C) and 120 hpf (B, D). Compared with control (B), BTS-treated embryos (D) showed a clear edema (indicated by the arrow) at 120 hpf. E and F. Anti-MyHC antibody (F59) staining shows the organization of thick filaments in slow muscles of control (E) or BTS-treated (F) embryos at 60 hpf. G and H. Anti-MLC antibody (F310) staining shows the organization of thick filaments in fast muscles of control (G) or BTS-treated (H) embryos at 72 hpf. I and J. Anti-α-actin antibody staining shows the organization of thin filaments in slow muscles of control (I) or BTS-treated (J) embryos at 60 hpf. K and L. Anti-α-actin antibody staining shows the organization of thin filaments in fast muscles of control (K) or BTS-treated (L) embryos at 72 hpf. Scale bars = 100 µm in A and B, 25 µm in E.</p

Efficacy of third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in advanced NSCLC with different T790M statuses tested via digital droplet polymerase chain reaction ddPCR and next-generation sequencing

We hypothesize that digital droplet polymerase chain reaction (ddPCR) would optimize the treatment strategies in epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) relapsed patients. In this study, we compared the efficacy of third-generation TKIs with various T790M statuses via ddPCR and next-generation sequencing (NGS). NGS was performed on blood samples of patients progressed from previous EGFR-TKIs for resistance mechanism. T790M-negative patients received further liquid biopsy using ddPCR for T790M detection. A cohort of 40 patients were enrolled, with 30.0% (12/40) T790M-positive via NGS (Group A). In another 28 T790M-negative patients by NGS, 11 (39.3%) were T790M-positive (Group B) and 17 (60.7%) were T790M-negative (Group C) via ddPCR. A relatively longer progression-free survival (PFS) was observed in group A (NR) and group B (10.0 months, 95% CI 7.040–12.889) than in group C (7.0 months, 95% CI 0.000–15.219), with no significant difference across all three groups (p = 0.196), or between group B and C (p = 0.412). EGFR-sensitive mutation correlated with inferior PFS (p = 0.041) and ORR (p = 0.326), and a significantly lower DCR (p = 0.033) in T790M-negative patients via NGS (n = 28). This study indicates that ddPCR may contribute as a supplement to NGS in liquid biopsies for T790M detection in EGFR-TKIs relapsed patients and help to optimize the treatment strategies, especially for those without coexistence of EGFR-sensitive mutation. www.clinicaltrials.gov identifier is NCT05458726.</p

Knockdown of <i>smyhc1</i> expression or <i>hsp90α1</i> mutation resulted in defective thin filament organization in skeletal muscles of zebrafish embryos.

<p>A–C. Anti-α−actin antibody staining shows the organization of thin filaments in slow muscles of control (A), <i>smyhc1</i> knockdown (B), or <i>slo^tu44c</i> mutant (C) embryos at 48 hpf. D, F. Anti-α−actin antibody staining shows the organization of thin filaments in fast muscles of control (D), <i>smyhc1</i> knockdown (E), or <i>slo^tu44c</i> mutant (F) embryos at 72 hpf. Scale bar = 25 µm in A.</p