Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non–small-cell lung cancer (NSCLC) with ALK ...rearrangement. However, the mechanisms of resistance remain largely unclear.
This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients’ clinicopathologic characteristics and treatment outcomes were analyzed.
Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%.
The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.
•We analyzed cfDNA and rebiopsied tumors by NGS after ALK inhibitor resistance.•ALK kinase domain mutations were found in less than one-third of patients.•At rebiopsy, adding cfDNA NGS to tissue NGS may increase mutation detection rate.•Compound mutations were found in crizotinib, ceritinib, and alectinib resistance.•Lorlatinib was not effective against compound ALK mutations in this cohort.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The regulation of RagAGTP is important for amino-acid-induced mTORC1 activation. Although GATOR1 complex has been identified as a negative regulator for mTORC1 by hydrolyzing RagAGTP, how GATOR1 is ...recruited to RagA to attenuate mTORC1 signaling remains unclear. Moreover, how mTORC1 signaling is terminated upon amino acid stimulation is also unknown. We show that the recruitment of GATOR1 to RagA is induced by amino acids in an mTORC1-dependent manner. Skp2 E3 ligase drives K63-linked ubiquitination of RagA, which facilitates GATOR1 recruitment and RagAGTP hydrolysis, thereby providing a negative feedback loop to attenuate mTORC1 lysosomal recruitment and prevent mTORC1 hyperactivation. We further demonstrate that Skp2 promotes autophagy but inhibits cell size and cilia growth through RagA ubiquitination and mTORC1 inhibition. We thereby propose a negative feedback whereby Skp2-mediated RagA ubiquitination recruits GATOR1 to restrict mTORC1 signaling upon sustained amino acid stimulation, which serves a critical mechanism to maintain proper cellular functions.
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•Skp2 mediates amino-acid-induced RagA ubiquitination and GATOR1 recruitment•Skp2 is a negative feedback regulator of amino-acid-dependent mTORC1 signaling•Skp2 promotes autophagy but inhibits cell size and cilia growth by mTORC1 repression
Jin et al. identify a critical molecular mechanism by which amino acids initiate a negative feedback loop for amino-acid-dependent mTORC1signaling. The findings demonstrate that mTORC1 signaling is properly restricted in the physiological condition under continuous amino acid stimulation, thus preventing mTORC1 hyperactivation and cellular functional disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives
To investigate the association of sarcopenia, myosteatosis, and sarcopenic obesity with survival outcomes among patients who underwent immunotherapy for advanced hepatocellular carcinoma ...(HCC).
Methods
In this retrospective analysis, patients who initiated immunotherapy for advanced HCC were enrolled. Sarcopenia and myosteatosis were evaluated on pretreatment CT at L3 level by skeletal muscle index and mean muscle attenuation using predefined cutoff values. Sarcopenic obesity was defined as concurrent sarcopenia and body mass index > 25 kg/m
2
. The log-rank test and the Cox proportional hazards model were used to compare overall survival (OS) and progression-free survival (PFS).
Results
A total of 138 patients was included (discovery cohort
n
= 111, validation cohort
n
= 27). In the discovery cohort, patients with sarcopenia exhibited significantly poorer PFS (
p
= 0.048) and OS (
p
= 0.002) than patients without sarcopenia. Patients with myosteatosis exhibited significantly poorer PFS (
p
< 0.001) and OS (
p
< 0.001) than patients without myosteatosis. Patients with sarcopenic obesity compared to patients without sarcopenic obesity exhibited significantly poorer OS (
p
= 0.006) but not PFS (
p
= 0.31). In multivariate analysis adjusting for patient demographics, tumor extent, and liver function reserve, myosteatosis remained an independent predictor of poor PFS (
p
= 0.014) and OS (
p
= 0.007); sarcopenia remained an independent predictor for poor OS (
p
= 0.007). The prediction models for survival outcomes built by the discovery cohort showed similar performance in the validation cohort.
Conclusions
Sarcopenia and myosteatosis are independent prognostic factors in patients who received immunotherapy for advanced HCC.
Key Points
• Sarcopenia and myosteatosis can be evaluated by CT at L3 level.
• Sarcopenia, myosteatosis, and sarcopenic obesity were associated with poor survival outcomes in patients who underwent immunotherapy for advanced HCC.
• Myosteatosis was an independent predictor of PFS and OS, and sarcopenia was independent for OS in these patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Abstract
We present Atacama Large Millimeter/submillimeter Array (ALMA) observations of the Class I source Oph IRS 63 in the context of the Early Planet Formation in Embedded Disks large program. Our ...ALMA observations of Oph IRS 63 show a myriad of protostellar features, such as a shell-like bipolar outflow (in
12
CO), an extended rotating envelope structure (in
13
CO), a streamer connecting the envelope to the disk (in C
18
O), and several small-scale spiral structures seen toward the edge of the dust continuum (in SO). By analyzing the velocity pattern of
13
CO and C
18
O, we measure a protostellar mass of
M
⋆
= 0.5 ± 0.2
M
⊙
and confirm the presence of a disk rotating at almost Keplerian velocity that extends up to ∼260 au. These calculations also show that the gaseous disk is about four times larger than the dust disk, which could indicate dust evolution and radial drift. Furthermore, we model the C
18
O streamer and SO spiral structures as features originating from an infalling rotating structure that continuously feeds the young protostellar disk. We compute an envelope-to-disk mass infall rate of ∼10
−6
M
⊙
yr
−1
and compare it to the disk-to-star mass accretion rate of ∼10
−8
M
⊙
yr
−1
, from which we infer that the protostellar disk is in a mass buildup phase. At the current mass infall rate, we speculate that soon the disk will become too massive to be gravitationally stable.
Mutations in genes involved in the production, migration, or differentiation of cortical neurons often lead to malformations of cortical development (MCDs). However, many genetic mutations involved ...in MCD pathogenesis remain unidentified. Here we developed a genetic screening paradigm based on transposon-mediated somatic mutagenesis by in utero electroporation and the inability of mutant neuronal precursors to migrate to the cortex and identified 33 candidate MCD genes. Consistent with the screen, several genes have already been implicated in neural development and disorders. Functional disruption of the candidate genes by RNAi or CRISPR/Cas9 causes altered neuronal distributions that resemble human cortical dysplasia. To verify potential clinical relevance of these candidate genes, we analyzed somatic mutations in brain tissue from patients with focal cortical dysplasia and found that mutations are enriched in these candidate genes. These results demonstrate that this approach is able to identify potential mouse genes involved in cortical development and MCD pathogenesis.
Adequate axillary lymph node (ALN) staging is critical for patients with invasive breast cancer. However, neoadjuvant chemotherapy (NAC) was associated with a lower risk of ALN metastasis compared ...with those who underwent primary surgery among clinically node-negative (cN0) patients. This study aimed to investigate the factors associated with ALN status among patients with cN0 breast cancer undergoing NAC. A total of 222 consecutive patients with cN0 breast cancer undergoing NAC between January 2012 and December 2021 were reviewed. Univariate and multivariate analyses were performed to compare factors associated with positive ALN status. Seventeen patients (7.7%) had ALNs metastases. Here, 90 patients (40.5%) achieved pathologic complete response in the breast (breast-pCR), and all had negative ALN status. Lymphovascular invasion (odds ratio: 29.366, p < 0.0001) was an independent risk predictor of ALN metastasis in all study populations. Among patients without breast-pCR, mastectomies were performed more frequently in patients with ALN metastasis (52.9%) than in those without metastasis (20.9%) (p = 0.013). Our findings support the omission of axillary surgery in patients who achieve breast-pCR. Prospective studies are needed to confirm the feasibility of a future two-stage surgical plan for breast-conserving surgery in patients who are likely to achieve breast-pCR during clinical evaluation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In this work, we report a series of bis-tridentate Ir(III) metal complexes, comprising a dianionic pyrazole-pyridine-phenyl tridentate chelate and a monoanionic chelate bearing a peripheral carbene ...and carboline coordination fragment that is linked to the central phenyl group. All these Ir(III) complexes were synthesized with an efficient one-pot and two-step method, and their emission hue was fine-tuned by variation of the substituent at the central coordination entity (i.e., pyridinyl and phenyl group) of each of the tridentate chelates. Their photophysical and electrochemical properties, thermal stabilities and electroluminescence performances are examined and discussed comprehensively. The doped devices based on Ir(cbF)(phyz1) (Cb1) and Ir(cbB)(phyz1) (Cb4) give a maximum external quantum efficiency (current efficiency) of 16.6% (55.2 cd/A) and 13.9% (43.8 cd/A), respectively. The relatively high electroluminescence efficiencies indicate that bis-tridentate Ir(III) complexes are promising candidates for OLED applications.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Stress-induced phosphoprotein 1 (STIP1), a cochaperone that organizes other chaperones, heat shock proteins (HSPs), was recently shown to be secreted by human ovarian cancer cells. In neuronal ...tissues, binding to prion protein was required for STIP1 to activate the ERK (extracellular-regulated MAP kinase) signaling pathways. However, we report that STIP1 binding to a bone morphogenetic protein (BMP) receptor, ALK2 (activin A receptor, type II-like kinase 2), was necessary and sufficient to stimulate proliferation of ovarian cancer cells. The binding of STIP1 to ALK2 activated the SMAD signaling pathway, leading to transcriptional activation of ID3 (inhibitor of DNA binding 3), promoting cell proliferation. In conclusion, ovarian-cancer-tissue-secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways. Although animal studies are needed to confirm these mechanisms in vivo, our results may pave the way for developing novel therapeutic strategies for ovarian cancer.
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► Ovarian cancer tissues secrete STIP1 into blood circulation ► rhSTIP1 may bind to BMP receptor ALK2 and activate the SMAD1/SMAD5-ID3 pathway ► The STIP1-ALK2 pathway stimulates cell proliferation in ovarian cancer cells
STIP1 is a cochaperone for heat shock proteins. When secreted by neuronal cells, STIP1 was shown to bind to prion membrane protein and activate ERK pathways. Herein, Chao, Wang, and colleagues report that the ovarian-cancer-tissue-secreted STIP1 binds to a BMP receptor, ALK2, to activate SMAD1/SMAD5 pathways and upregulate ID3 expression, leading to cancer cell proliferation. These results not only provide insights into the tumorigenesis of ovarian cancer but also pave the way for developing novel therapeutic strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The prevalence of lower limb lymphoedema and its impact in gynaecological cancer patients is underestimated. However, a valid and reliable scale to measure lower leg lymphoedema in Taiwan has not ...been available. The purpose of the study was to translate the English version of Lymphoedema Functioning, Disability and Health Questionnaire for Lower Limb Lymphoedema into a Chinese version (Lymph‐ICF‐LL‐C), and evaluate the psychometric properties of the Lymph‐ICF‐LL‐C in Taiwanese women with gynaecological cancer surgery. A total of 170 women with gynaecological cancer surgery were recruited to examine the Lymph‐ICF‐LL‐C. The Lymph‐ICF‐LL‐C shows satisfactory internal consistency (Cronbach's alphas ≥ 0.84) and stability test–retest reliability (Intraclass correlation coefficient ≥0.55–0.90) at a 2‐week interval. Exploratory factor analysis showed that 68.53% of the total variance was explained by a five‐factor solution. The concurrent validity of the Lymph‐ICF‐LL‐C was evidenced by a significant correlation with a fatigue scale (r = 0.46, p < 0.01) and with the bilateral difference of lower limb circumference (r = 0.24–0.36, all p < 0.01). The Lymph‐ICF‐LL‐C can be used for assessing the life impact of lower limb lymphoedema, allowing appropriate interventions to prevent further deterioration and complications.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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