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Fitness of cells is dependent on protein homeostasis which is maintained by cooperative activities of protein chaperones and proteolytic machinery. Upon encountering protein-damaging conditions, cells activate the heat-shock response (HSR) which involves HSF1-mediated transcriptional upregulation of a group of chaperones - the heat shock proteins (HSPs). Cancer cells experience high levels of proteotoxic stress due to the production of mutated proteins, aneuploidy-induced excess of components of multiprotein complexes, increased translation rates, and dysregulated metabolism. To cope with this chronic state of proteotoxic stress, cancers almost invariably upregulate major components of HSR, including HSF1 and individual HSPs. Some oncogenic programs show dependence or coupling with a particular HSR factor (such as frequent coamplification of HSF1 and MYC genes). learn more Elevated levels of HSPs and HSF1 are typically associated with drug resistance and poor clinical outcomes in various malignancies. The non-oncogene dependence ("addiction") on protein quality controls represents a pancancer target in treating human malignancies, offering a potential to enhance efficacy of standard and targeted chemotherapy and immune checkpoint inhibitors. In cancers with specific dependencies, HSR components can serve as alternative targets to poorly druggable oncogenic drivers.
Conventional parameters show limited and unreliable correlations with medulloblastoma prognosis.
To evaluate the factors influencing overall survival (OS), event-free survival (EFS), and progression-free survival (PFS) in patients with medulloblastoma.
PubMed, EMBASE, the Cochrane Library, and Web of Science were searched for studies published up to May 2021. The associations between various clinical and treatment factors and survival parameters were assessed.
Twenty-nine studies (8455 patients) were included. Desmoplastic medulloblastoma (HR=0.41, 95%CI 0.31-0.56), M0 disease (HR=2.07, 95%CI 1.48-2.89), WNT, SSH, group 4 (all P<0.05 vs. group 3), GTR vs. STR (HR=1.37, 95%CI 1.04-1.08), radiotherapy (HR=0.45, 95%CI 0.20-0.80), craniospinal irradiation (HR=0.49, 95%CI 0.38-0.64), and high 5hmC levels (HR=2.90, 95%CI 1.85-4.55) were associated with a better OS. WNT, SSH, group 4 (all P<0.05 vs. group 3), residual tumor ≤1.5 cm
(HR=2.08, 95%CI 1.18-3.68), GTR vs. STR (HR=1.31, 95%CI 1.03-1.68), craniospinal irradiation (HR=0.46, 95%CI 0.37-0.57), high 5hmC levels (HR=3.10, 95%CI 2.01-4.76), and <49 days between resection and radiotherapy (HR=2.54, 95%CI 1.48-4.37) were associated with better PFS. Classic vs. desmoplastic medulloblastoma (HR=1.81, 95%CI 1.04-3.16), SSH, WNT (both P<0.05 vs, non-SSH/non-WNT), GTR vs. STR (HR=2.01, 95%CI 1.42-2.85), and radiotherapy (HR=0.31, 95%CI 0.15-0.64) were associated with a better EFS.
Histology, molecular subgroup, GTR, and radiotherapy are significantly associated with survival parameters in patients with medulloblastoma. Nevertheless, high-quality prospective cohort studies are necessary to improve the conclusions.
Histology, molecular subgroup, GTR, and radiotherapy are significantly associated with survival parameters in patients with medulloblastoma. Nevertheless, high-quality prospective cohort studies are necessary to improve the conclusions.Myeloid sarcoma is a rare extramedullary tumor of immature myeloid cells. Certain known acute myeloid leukemia cytogenetic abnormalities, in particular t(8,21), has been associated with a higher incidence. Myeloid sarcoma, which rarely happens in acute promyelocytic leukemias, is more common in recurrent patients after the advent of all-trans retinoic acid (ATRA) and are rare in untreated acute promyelocytic leukemia. We described a case of, to our knowledge, de novo myeloid sarcoma of the spine confirmed as acute promyelocytic leukemia. Myeloid sarcoma is diagnosed by spinal tumor biopsy, and microscopic examination of a bone marrow smear and cytogenetic analysis led to a confirmed diagnosis of acute promyelocytic leukemia.Prioritization of immunogenic neoantigens is key to enhancing cancer immunotherapy through the development of personalized vaccines, adoptive T cell therapy, and the prediction of response to immune checkpoint inhibition. Neoantigens are tumor-specific proteins that allow the immune system to recognize and destroy a tumor. Cancer immunotherapies, such as personalized cancer vaccines, adoptive T cell therapy, and immune checkpoint inhibition, rely on an understanding of the patient-specific neoantigen profile in order to guide personalized therapeutic strategies. Genomic approaches to predicting and prioritizing immunogenic neoantigens are rapidly expanding, raising new opportunities to advance these tools and enhance their clinical relevance. Predicting neoantigens requires acquisition of high-quality samples and sequencing data, followed by variant calling and variant annotation. Subsequently, prioritizing which of these neoantigens may elicit a tumor-specific immune response requires application and integration of tools to predict the expression, processing, binding, and recognition potentials of the neoantigen. Finally, improvement of the computational tools is held in constant tension with the availability of datasets with validated immunogenic neoantigens. The goal of this review article is to summarize the current knowledge and limitations in neoantigen prediction, prioritization, and validation and propose future directions that will improve personalized cancer treatment.
Rearrangements of Anaplastic lymphoma kinase (
) have been discovered as a novel driver mutation in patients with non-small-cell lung cancer (NSCLC). Patients' responses to ALK tyrosine kinase inhibitors (TKIs) may vary depending on the variations of
rearrangements they have. It is imperative for clinicians to identify druggable
fusions in routine practice.
In this study, we discovered a rare
rearrangement type (
) in a Chinese lung adenocarcinoma patient who responded well to ALK inhibitor SAF-189s. The positive expression of ALK in lung biopsy tissue was verified by IHC analysis. A new
fusion was discovered using NGS. The patient was treated with SAF-189s (160 mg per day) as a first-line therapy and went into continuous remission, with a 12 months progression-free survival at the last follow-up.
This is the first case of
fusion with an excellent response to an ALK inhibitor, which will provide better understanding of ALK-TKI applications for NSCLC patients with
fusion in the future.
This is the first case of SDK1-ALK fusion with an excellent response to an ALK inhibitor, which will provide better understanding of ALK-TKI applications for NSCLC patients with ALK fusion in the future.
Circulating rare cells (CRCs) are known as a crucial nucleated cellular response to pathological conditions, yet the landscape of cell types across a wide variety of diseases lacks comprehensive understanding. This study aimed at detecting and presenting a full spectrum of highly heterogeneous CRCs in clinical practice and further explored the characterization of CRC subtypes in distinct biomarker combinations and aneuploid chromosomes among various disease groups.
Peripheral blood was obtained from 2,360 patients with different cancers and non-neoplastic diseases. CRC capture and identification were accomplished using a novel platform integrating subtraction enrichment and immunostaining-fluorescence
hybridization (SE-iFISH) strategy with a high-throughput automated image scanning system, on which hemocyte, tumor, epithelial, endothelial, mesenchymal, and stemness biomarkers were immunostained and displayed simultaneously. Double chromosome enumeration probe (CEP8 and CEP12) co-detection was performedg platform, along with the comprehensive atlas, offer insight into the heterogeneity of CRCs and reveal potential contributions to specific disease diagnosis and therapeutic target cell discovery.
The alternative biomarkers and chromosomes to be targeted by SE-iFISH and the image scanning platform, along with the comprehensive atlas, offer insight into the heterogeneity of CRCs and reveal potential contributions to specific disease diagnosis and therapeutic target cell discovery.
Small cell lung cancer (SCLC) has recently been characterized as heterogeneous tumors due to consensus nomenclature for distinct molecular subtypes on the basis of differential expression of four transcription markers (ASCL1, NEUROD1, POU2F3, and YAP1). It is necessary to validate molecular subtype classification in primary SCLC tumors by immunohistochemical (IHC) staining and investigate its relevance to survival outcomes.
Using a large number of surgically resected primary SCLC tumors, we assessed the mRNA and protein levels of the four subtype markers (ASCL1, NEUROD1, POU2F3 and YAP1) in two independent cohorts, respectively. Next, molecular subtypes defined by the four subtype markers was conducted to identify the association with clinicopathologic characteristics, survival outcomes, the expression of classic neuroendocrine markers, and molecules related to tumor immune microenvironment.
Samples were categorized into four subtypes based on the relative expression levels of the four subtype markers, and protein levels from primary SCLC tumors. The molecular subtypes determined by IHC could be a pre-selected effective biomarker significantly influenced on prognosis in patients with SCLC, which warrants further studies to provide better preventative and therapeutic options for distinct molecular subtypes.
We validated the new molecular subtype classification and clinical relevance on both mRNA and protein levels from primary SCLC tumors. The molecular subtypes determined by IHC could be a pre-selected effective biomarker significantly influenced on prognosis in patients with SCLC, which warrants further studies to provide better preventative and therapeutic options for distinct molecular subtypes.
Malnutrition is recognized as a risk factor for poor outcome in patients with gastric cancer (GC). In 2018, the Global Leadership Initiative on Malnutrition (GLIM) published standardized criteria for the diagnosis of malnutrition. Our aim was to investigate whether any of the components of the GLIM diagnostic criteria were related to worse clinical outcomes in patients with GC.
This study analyzed patients with GC who underwent radical gastrectomy in our hospital between 2014 and 2019. A preoperative nutritional assessment was performed for each patient. Matching was based on the presence of three GLIM components high weight loss (WL), low body mass index (BMI), and low skeletal muscle index (SMI).
The analysis included 1,188 patients, including 241 (20.3%) with high WL, 156 (13.1%) with low BMI, and 355 (29.9%) with low SMI. Before matching, patients who met the GLIM component criteria were mostly associated with older age, low nutritional reserves, and late tumor progression. After matching, the clinical characteristics of the three cohorts were balanced. In the matched queue, the survival prognosis of the high WL group was worse than that of the non-WL group, and the postoperative complication rate was higher in the low SMI group than in the normal SMI group (P <0.05). In addition, the clinical outcomes in the low and normal BMI groups were similar (P >0.05).
Of the GLIM criteria, high WL and low SMI may be associated with poor clinical outcomes in patients with GC, while a low BMI may not be associated with outcome.
Of the GLIM criteria, high WL and low SMI may be associated with poor clinical outcomes in patients with GC, while a low BMI may not be associated with outcome.