A number of mutations in key oncogenes have been identified as important for the initiation and maintenance of lung adenocarcinoma (LAC). This study elucidated the prevalence and prognostic ...significance of mutations in the epidermal growth factor receptor gene (
) and rearrangements in the anaplastic lymphoma kinase gene (
) in patients with surgically resected primary LAC.
We retrospectively analyzed 675 consecutive patients who underwent radical resection at a single institution. We concurrently analyzed mutations in
and the Kirsten rat sarcoma viral oncogene homolog gene (
) by reverse transcription (RT)-PCR, and investigated
rearrangements by immunohistochemistry. LAC with or without various oncogenic mutations was studied for clinicopathological features and their association with disease-free survival (DFS) and overall survival (OS).
rearrangements and
mutations were detected in 75 and 312 patients, respectively, with coexistence in 5 cases.
rearrangements and mutations in
and
were mutually exclusive. Compared with patients with
mutations,
rearrangements were more common in younger patients, and those with advanced tumors, lymph node metastases, and higher rates of postoperative adjuvant therapy. Histologically,
mutations were more common than
rearrangements in patients with the acinar predominant subtype and the lepidic predominant subtype of LAC, whereas
rearrangements were more frequent in the solid predominant subtype with mucin production and invasive mucinous adenocarcinomas.
-positive patients had a significantly worse DFS than those with
mutations and wild-type (WT) patients. The mean OS after surgical procedures was significantly longer in
-mutated versus WT patients. No significant differences were found in patients with
-positive tumors compared with
-mutated and WT patients.
Clinicopathological features of LAC with
rearrangements differ from those of LAC with
mutations. Patients with
rearrangements had a significantly worse DFS than those harboring
mutations. Thus,
rearrangements are an adverse prognostic factor in surgically-resected LAC patients, while
mutations are associated with a better prognosis.
A 47‐year‐old female with ALK‐rearranged lung adenocarcinoma developed leptomeningeal metastasis (LM) after progression on first‐line crizotinib. Alectinib 300 mg was commenced and the patient ...achieved clinical and radiographic improvements. After nine months of alectinib 300 mg, she started to experience symptomatic LM. Two concurrent non‐EML4‐ALK rearrangements, LOC388942‐ALK and LINC00211‐ALK, were identified from the CSF but not from the plasma samples. With the primary lung lesions remaining stable, the alectinib dose was increased to 600 mg twice daily which alleviated the clinical symptoms of symptomatic LM. After 7.6 months of alectinib 600 mg, the patient again experienced CNS progression. With both CSF and plasma samples revealing no druggable mutations, the alectinib dose was re‐escalated to 900 mg twice daily, resulting in clinical benefits lasting for two months. Her therapy was then switched to lorlatinib which controlled the disease for 8.7 months until her demise. The LINC00211‐ALK fusion, which retains the ALK kinase domain, detected from the CSF was the mechanism of treatment efficacy in this patient. The central nervous system (CNS) has been increasingly recognized as a site of treatment failure in multiple cancers, including non‐small cell lung cancer (NSCLC). Our case demonstrated that alectinib dose‐escalation and lorlatinib overcame ALK inhibitor resistance in the CNS in an ALK‐positive LM patient. Furthermore, we provide the first clinical evidence of the efficacy of sequential ALK inhibitors in targeting LINC00211‐ALK in a patient with LM.
PD‐1 is highly expressed on tumor‐infiltrated antigen‐specific T cells and limit the antitumor function. Blocking of PD‐1/PD‐L1 signaling has shown unprecedented curative efficacies in patients with ...advanced cancer. However, only a limited population of patients benefited from such therapies. Our study aimed to explore biological properties, functional regulation and reversal of MAGE‐A3‐specific CD8+ T cells in patients with esophageal squamous cell carcinoma (ESCC). The underlying principle of deficiency and restoring MAGE‐A3‐specific CD8+ T cells function in tumor microenvironment (TME) was evaluated. MAGE‐A3‐specific CD8+ T cells could lyse HLA‐A2+/MAGE‐A3+ tumor cells. Tetramer+ T cell frequency was higher in elder patients, but lower in patients with lymph node metastasis and late tumor stage (p < 0.05). CD107ahigh expression on functional T cells was an independent prognostic factor in Cox regression analysis. PD‐1 was highly expressed on dysfunctional antigen‐specific CD8+ T cells and tumor infiltrating T lymphocytes (p < 0.05). Myeloid‐derived suppressor cells (MDSCs) derived‐TGF‐β mediated PD‐1high expression on CD8+ T cells, which led to be resistance to PD‐1/PD‐L1 blockade in TME. Dual PD‐1/PD‐L1 and TGF‐β signaling pathway blockades synergistically restored the function and antitumor ability of antigen‐specific CD8+ T cells in vitro/vivo assay. The presence of functional MAGE‐A3‐specific CD8+ T cells had an independent prognostic impact on survival of patients with ESCC. Furthermore, MDSCs‐derived TGF‐β increased PD‐1 expression on T cells and decreased the sensitivity to PD‐1/PD‐L1 blockade. Combining T cell‐based therapy with dual PD‐1/PD‐L1 and TGF‐β signaling pathway blockade could be considered a promising strategy for cancer treatment.
What's new?
MAGE‐A3 is one of the most frequently expressed cancer germline genes and a potential target for cancer immunotherapy. Here the authors show that the frequency of functional MAGE‐A3‐specific CD8+ T cells is an independent prognostic factor in patients with esophageal squamous cell carcinoma. The exhaustion marker PD‐1 was highly expressed on dysfunctional antigen‐specific CD8+ T cells and tumor‐infiltrating T lymphocytes but anti‐tumor function was restored upon dual blockade of PD‐1/PD‐L1 and TGF‐β signaling pathways, a strategy the authors recommend to explore further in esophageal cancer immunotherapy.
Background
Most of the current progression of immune checkpoint inhibitors for malignant melanoma is based on data from Caucasians in Western countries, but the benefit of Chinese patients is ...limited, mainly due to different pathological subtypes. The patients in western countries are mainly skin melanoma (about 90%), while the acral and mucosal types are dominant in China, accounting for 41.8% and 22.6% respectively. Acral and mucosal melanoma have lower response rates to immunotherapy and chemotherapy.
Objective
Whether immune checkpoint inhibitors can improve the survival of Chinese patients with malignant melanoma, therefore, we conducted a retrospective analysis.
Methods
We analyzed 53 patients with metastatic melanoma treated in our hospital to evaluate the efficacy and safety of PD‐1 mAb in Chinese patients with metastatic melanoma, and performed univariate and multivariate analyses of prognostic factors that may affect overall survival (OS).
Results
In a study of 125 patients with advanced malignant melanoma, 53 patients participated, with a median follow‐up of 16 months. Among these, 69.8% died, and 30.2% remained on treatment. Median progression‐free survival (PFS) was 6 months, and median OS was 19 months. Patients treated with immune checkpoint inhibitors had improved outcomes, with a median PFS of 7 months and a median OS of 24 months. Patients with bone metastasis and aberrant Lactate dehydrogenase (LDH) post‐treatment had worse prognoses, while immunotherapy was a protective factor. Subgroup analysis showed the benefits of immunotherapy across various patient characteristics. No unexpected toxicities were observed.
Conclusion
The study highlights the efficacy of immune checkpoint inhibitors, particularly PD‐1 mAb, in improving survival outcomes for Chinese patients with metastatic melanoma.
Background and Purpose
Chemotherapy‐induced neuropathic pain (CINP) currently has limited effective treatment. Although the roles of oxytocin (OXT) and the oxytocin receptor (OXTR) in central ...analgesia have been well documented, the expression and function of OXTR in the peripheral nervous system remain unclear. Here, we evaluated the peripheral antinociceptive profiles of OXTR in CINP.
Experimental Approach
Paclitaxel (PTX) was used to establish CINP. Quantitative real‐time polymerase chain reaction (qRT‐PCR), in situ hybridization, and immunohistochemistry were used to observe OXTR expression in dorsal root ganglia (DRG). The antinociceptive effects of OXT were assessed by hot‐plate and von Frey tests. Whole‐cell patch clamp was performed to record sodium currents, excitability of DRG neurons, and excitatory synapse transmission.
Key Results
Expression of OXTR in DRG neurons was enhanced significantly after PTX treatment. Activation of OXTR exhibited antinociceptive effects, by decreasing the hyperexcitability of DRG neurons in PTX‐treated mice. Additionally, OXTR activation up‐regulated the phosphorylation of protein kinase C (pPKC) and, in turn, impaired voltage‐gated sodium currents, particularly the voltage‐gated sodium channel 1.7 (NaV1.7) current, that plays an indispensable role in PTX‐induced neuropathic pain. OXT suppressed excitatory transmission in the spinal dorsal horn as well as excitatory inputs from primary afferents in PTX‐treated mice.
Conclusion and Implications
The OXTR in small‐sized DRG neurons is up‐regulated in CINP and its activation relieved CINP by inhibiting the neural excitability by impairment of NaV1.7 currents via pPKC. Our results suggest that OXTR on peripheral sensory neurons is a potential therapeutic target to relieve CINP.
Melanoma-associated Ag (MAGE)-C2, an immunogenic cancer germline (testis) Ag, is highly expressed by various tumor cells, thymic medullary epithelial cells, and germ cells. In this study, we aimed to ...explore the immunologic properties of MAGE-C2-specific CD8
T cells and the relationship of its TCR β-chain V region (TCR vβ) subfamily distribution to prognosis of patients with esophageal cancer. PBMCs and tumor-infiltrating lymphocytes expanded by CD3/CD28 Dynabeads and MAGE-C2 peptides in vitro resulted in the induction of lysosome-associated membrane protein-1 (LAMP-1 or CD107a) on the cell surface and the production of IFN-γ by MAGE-C2-specific CD8
T cells. We found differential TCR vβ subfamily distribution among flow-sorted CD107a
IFN-γ
and CD107a
IFN-γ
CD8
T cells. The proportion of CD107a
and/or IFN-γ
tetramer
CD8
T cells was lower in patients with lymph node metastasis, late tumor stage, and poorly differentiated state (
< 0.05). T-box transcription factor was positively correlated with CD107a and IFN-γ. Kaplan-Meier analysis showed that patients whose MAGE-C2-specific CD8
T cells expressed high CD107a and/or IFN-γ had a longer survival time when compared with patients whose MAGE-C2-specific CD8
T cells expressed low levels of CD107a and/or IFN-γ. Moreover, analysis of TCR vβ subfamily distribution revealed that a higher frequency of TCR vβ16 in MAGE-C2-specific CD8
T cells was positively correlated with a better prognosis. These results suggest that the presence of functional MAGE-C2-specific CD8
T cells had an independent prognostic impact on the survival of patients with esophageal cancer.
As the unique power-discharging channel for high-speed trains, the 'train-rail' mobile coupling grounding system plays a vital role in sending the traction power back to the terrestrial substations, ...through the electrical contact between the rotating wheel and the steel rail. The whole system is composed of two kinds of grounding modes: working grounding is in charge of draining the traction power into the rail track; the protective grounding provides the reference grounding potential for the vehicle-mounted equipment. Different from the fixed terrestrial grounding technique normally implemented in power system, when the relative motion occurs between the train and the rail, both the 'catenary-to-train' and 'train-to-ground' impedances vary transiently, which may lead to the current flowing through each grounding wheel varying unpredictably. Herein, the 'catenary-train-rail' mobile coupling grounding model was built based on the equivalent circuit modeling technique for evaluating the transiently-varying tendency of the grounding impedances and currents flowing through each grounding wheel. To cope with different operational conditions, the adjustable grounding impedance methodology is firstly proposed for adapting the unpredictable variation of the grounding impedance, when the relative motion occurs between the train and the rail. Ultimately, the validity of the novel grounding system applying the adjustable grounding impedance technology is verified under different operational conditions, with the consideration of both TB current and voltage.
When a high-speed train approaches an insulated split-phase section embedded between neighboring power supply arms carrying powers with different phases, the vehicle-mounted vacuum circuit breaker ...(VCB) needs to be switched off to avoid short-circuit fault during the phase-changing procedure. At the moment of switching the VCB contacts, the arc is triggered easily, accompanying with overvoltage impulse. As the core of the whole system, the traction transformer frequently suffers the invasion of the overvoltage impulse, which possibly causes partial discharge or breakdown accidents. To evaluate the impact of overvoltage on the transformer, it is essential to observe the overvoltage distribution at different positions in the transformer. As an equivalent circuit (EC) model of the traction transformer involving the spatially distributed capacitance is built based on the improved capacitor network methodology (ICNM), the partial discharge risk in the transformer has been assessed. Ultimately, the multiphysics coupling models based on the finite-element method (FEM) have been launched to observe the specific distribution of the multiphysics field for verifying the validity of an EC model based on ICNM. These works lay the theoretical foundation for guiding the design of insulation and the thermal dissipation settings of the traction transformer, considering the threat brought from impulse.
The mobile distributed grounding system plays an irreplaceable role in discharging power for intercity trains, including two types of grounding settings (GSs): the working GS provides the pathway for ...discharging the traction current; the protective GS provides the reference grounding potential for the vehicle-mounted equipment. As both working and protective GSs share the rail as the common current-releasing pathway, the traction current released by working GSs might return the carriage through the adjacent protective GSs, forming as the train body (TB) current which threatens the vehicle-mounted electrical equipment. Herein, an equivalent circuit of the mobile distributed grounding system is built to analyze the TB current. For evaluating the influence brought by TB current on the vehicle-mounted equipment, a 3D finite element (FEM) geometry is launched, meanwhile the comparison of the multi-physical distributions is undertaken when applying different grounding layouts, with the emphasis of the highlighted region containing critical devices.
Esophageal cancer (EC) is one of the most common digestive malignant tumors worldwide. Over the past decades, there have been minimal improvements in outcomes for patients with EC. New targets and ...novel therapies are needed to improve outcomes for these patients. This study aimed to explore the molecular mechanisms of EC by integrated bioinformatic analyses of the feature genes associated with EC and correlative gene functions which can distinguish cancerous tissues from non-cancerous tissues. Gene expression profile GSE20347 was downloaded from Gene Expression Omnibus (GEO) database, including 17 EC samples and their paired adjacent non-cancerous samples. The differentially expressed genes (DEGs) between EC and normal specimens were identified and then applied to analyze the GO enrichment on gene functions and KEGG pathways. Corresponding Pathway Relation Network (Pathway-net) and Gene Signal Network (signal-net) of DEGs were established based on the data collected from GCBI datasets. The results showed that DEGs mainly participated in the process of cell adhesion, cell proliferation, survival, invasion, metastasis and angiogenesis. Aberrant expression of PTK2, MAPK signaling pathway, PI3K-Akt signaling pathway, p53 signaling pathway and MET were closely associated with EC carcinogenesis. Importantly, Interleukin 8 (IL8) and C-X-C chemokine receptor type 7 (CXCR-7) were predicted to be significantly related to EC. These findings were further validated by analyzing both TCGA database and our clinical samples of EC. Our discovery provides a registry of genes and pathways that are disrupted in EC, which has the potential to be used in clinic for diagnosis and target therapy of EC in future.
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