BackgroundHuman epidermal growth factor receptor 2 (HER2)-mutated lung cancer is a rare and aggressive subtype of non-small cell lung cancer (NSCLC), characterized by poor prognosis and limited response to conventional therapies. Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody-drug conjugate (ADC), has shown promising results in HER2-mutated cancers. However, its safety and efficacy in patients with renal dysfunction requiring continuous renal replacement therapy (CRRT) remain unclear.Case summaryA 69-year-old female with advanced HER2-mutant NSCLC developed acute kidney injury (AKI) requiring intermittent CRRT after failing standard chemotherapy. With strong patient commitment, T-DXd was initiated following multidisciplinary discussion. Although severe myelosuppression occurred following targeted therapy, it resolved with appropriate supportive care. Notably, no significant toxicities such as interstitial lung disease, hepatotoxicity, or further nephrotoxicity were observed. After three cycles of T-DXd, symptomatic improvement was achieved, including resolution of abdominal distension, significant reduction of ascites, and disappearance of hematuria. Follow-up imaging studies confirmed stable disease. Unfortunately, the patient succumbed to aspiration, which precluded administration of further T-DXd cycles.ConclusionT-DXd treatment in this CRRT-dependent patient with HER2-mutant lung cancer achieved disease control with manageable toxicity. While demonstrating potential clinical utility, the short survival period warrants cautious interpretation. Further validation is needed to establish its role in this population.

ObjectiveTo describe the clinical characteristics, treatment course, and management challenges of advanced pulmonary lymphoepithelioma-like carcinoma (LELC), with a focus on metastatic disease and treatment-interfering complications.MethodsWe report the clinical course of a 42-year-old woman with EBV-associated pulmonary LELC. The patient was initially diagnosed with stage IIIB disease and underwent radical surgery followed by adjuvant chemoradiotherapy. No definite local recurrence was observed postoperatively; however, cervical lymph node metastasis developed shortly thereafter, followed by rapid progression to stage IV disease characterized predominantly by liver metastases. First-line treatment with pembrolizumab combined with chemotherapy achieved an initial partial response. During subsequent disease progression, the patient developed persistent high-grade fever refractory to antimicrobial therapy, which significantly compromised treatment continuity.ResultsThis case demonstrates the potentially aggressive and heterogeneous clinical behavior of pulmonary LELC despite multimodal therapy. Serial plasma EBV-DNA levels closely paralleled disease activity, decreasing during treatment response and increasing during progression. Persistent high-grade fever posed a major diagnostic and therapeutic challenge. Tumor-related fever was considered the most likely etiology, although occult infection could not be definitively excluded. Due to sustained fever, declining performance status, limited clinical experience with immunotherapy at that time, and concerns regarding treatment-related risks, immunotherapy was interrupted during the febrile period.ConclusionAdvanced pulmonary LELC may exhibit aggressive clinical behavior with predominant metastatic burden. Immunochemotherapy may provide meaningful but often transient benefit in patients with high PD-L1 expression, while dynamic plasma EBV-DNA monitoring may serve as a useful indicator of disease activity. In addition, atypical tumor-related fever may substantially interfere with treatment continuity and clinical decision-making. Early recognition and proactive management of such complications may help optimize outcomes.

Acquired resistance represents a fundamental obstacle limiting the long-term efficacy of cancer chemotherapy. In T-cell acute lymphoblastic leukemia (T-ALL), the nucleoside analog prodrug nelarabine is a critical salvage therapy for relapsed/refractory (R/R) patients; however, resistance is common and rapid, worsening prognosis. The molecular mechanisms underlying this process remain largely to be elucidated. Here, we identify the oncogene MYC as a key functional mediator driving nelarabine resistance. Through unbiased transcriptomic profiling and functional validation, we demonstrate that nelarabine-resistant T-ALL cells develop a profound addiction to a hyperactive MYC transcriptional program. Critically, MYC knockdown restores nelarabine sensitivity, causally linking MYC to the resistant phenotype. While this discovery reveals a therapeutic vulnerability, MYC itself is considered an 'undruggable' protein, making direct inhibition a formidable challenge. We therefore pursued an indirect strategy, employing BET family protein degraders to dismantle the upstream epigenetic machinery essential for MYC transcription. Consistent with a MYC-driven mechanism, treatment with ARV-771 and ARV-825 induced potent degradation of BET proteins, suppressed MYC transcription, and profoundly impaired the viability and proliferation of nelarabine-resistant cells. Importantly, this strategy showed strong therapeutic efficacy in an in vivo model of nelarabine-resistant T-ALL, significantly reducing leukemia burden and extending survival. Our work establishes the first mechanistic link between nelarabine resistance and MYC dependency, providing a compelling preclinical rationale and therapeutic strategy to overcome this challenge. Collectively, this study offers a paradigm for reversing chemotherapy resistance by exploiting acquired transcriptional addictions. Trial Registration: Registry and the Registration No. of the study/trial. Yes, approved number: IRB Approval No.: Med-Ethics [2026] IIT No. (19).

This study aimed to compare the survival outcomes of paclitaxel liposome-based chemoradiotherapy, with or without rhEndostatin, in patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC). Patients with ESCC treated with paclitaxel liposome-based definitive chemoradiotherapy (dCRT), with or without rhEndostatin (E), between February 2015 and June 2020 were included. Patients received induction chemotherapy followed by concurrent chemoradiotherapy, with or without rhEndostatin. The chemotherapy regimen consisted of platinum-based doublet (paclitaxel liposome + cisplatin/nedaplatin). RhEndostatin was administered at a dose of 30 mg/d from day 1 to day 5 of each chemotherapy cycle. Total radiotherapy dose was 66–68 Gy, delivered in fractions of 2.0–2.2 Gy/d. Follow-up continued until December 2023. The primary endpoints were 3-year progression-free survival (PFS) rate. Secondary endpoints included 3-year overall survival (OS) rate, objective response rate (ORR), disease control rate (DCR), and toxicity. A total of 80 patients were included, with 34 in the dCRT group and 46 in the E + dCRT group. The 3-year PFS was 26.47

Resistance to Nelarabine, the primary FDA-approved therapy for relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL), is a major obstacle in this high-risk pediatric malignancy. To identify alternative therapies, we have developed two nelarabine-resistant T-ALL cell models and utilized the Connectivity Map (CMap) database to screen for compounds reversing resistance-associated expression profiles., Among the inhibitors screened, gemcitabine emerged as a lead candidate by inhibiting cell proliferation, inducing apoptosis, and suppressing DNA replication in resistant T-ALL cells. RNA sequencing revealed global transcriptomic changes in cells treated with gemcitabine, which were further validated by qRT-PCR. Critically, gemcitabine effectively controlled bone marrow tumor growth in an NSG mouse model with good tolerability. These findings highlight the potential of gemcitabine as a promising therapeutic strategy to overcome nelarabine-resistance in T-ALL.

Cyclin K (CCNK) has been identified as a promising antitumor target. However, the existing CCNK degraders have the defect of metabolic instability, which hinders their development as antitumor agents. Using a metabolically oriented scaffold hopping strategy based on HQ461 and NCT02, we developed ZLY025─a highly potent CCNK degrader (DC50 = 42.7 nM, Dmax >93%). It exhibits broad-spectrum antitumor activity, high kinase selectivity, excellent metabolic stability, and favorable oral pharmacokinetics (T1/2 = 6.82 h). Moreover, ZLY025 induced the highly selective degradation of CCNK with low off-target degradation effects in TMT-based global proteomic analysis. In the xenografted model, ZLY025 exerted robust antitumor activity by effectively degrading CCNK. In the subacute toxicity study, ZLY025 exhibited adequate safety profiles even at the sustaining high dose of 200 mg/kg. Based on these positive results, ZLY025 is worthy of further evaluation as the first highly potent and orally available CCNK molecular glue degrader.

Diffuse large B cell lymphoma (DLBCL) presents a great challenge in the clinic due to its poor prognosis. Prior research has identified c-Myc as a promising therapeutic target in DLBCL; however, direct targeting of c-Myc protein has proven challenging. The bromodomain and extraterminal (BET) protein family, which acts as transcriptional and epigenetic regulators, plays a crucial role in super-enhancer organization and transcriptional regulation of oncogenic drivers like c-Myc, offering an alternative approach. Recently developed BET proteolysis targeting chimera (PROTAC) compounds can rapidly and effectively degrade BET proteins and potentially offer a more durable effect than traditional BET inhibitors. In this work, we compared the anti-tumor activity of a BET PROTAC, ARV-825, with a BET inhibitor, JQ1, in DLBCL. Cell proliferation was assessed by CCK-8 assay, apoptosis was evaluated by Annexin V/PI staining, and the cell cycle was analyzed by staining DNA with propidium iodide (PI). Western blotting was used to determine the expression levels of BET family proteins and its downstream regulatory gene c-Myc, and the in vivo SCID mouse model implanted with SU-DHL-4 cells was used to analyze the in vivo drug efficacy. Our results showed that ARV-825 was superior to JQ1 in inhibiting DLBCL cell proliferation, inducing apoptosis, promoting cell cycle arrest, and prolonging survival. Notably, ARV-825 was more effective at downregulating c-Myc and BET protein levels than JQ1 in both in vitro and in vivo experiments. These evidences suggest that BET-PROTACs may offer a promising novel strategy for the clinical treatment of DLBCL.

BACKGROUND:Ultraviolet (UV) B can reach the epidermis and superficial dermis of the skin, inducing sunburn, inflammation, immunosuppression, cancer, and so on. Our former research found that receptor interacting protein (RIP) 1 could be upregulated in human dermal fibroblasts(HDFs) after UVB irradiation by using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry techniques. Besides, our further research found that RIP1 was involved in the UVB-induced production of ROS and MMPs in HDFs. So far, the mechanisms of skin photodamage induced by UV mainly include DNA damage, oxidative stress, inflammation, apoptosis, and necroptosis. The NF-κB pathway can be activated eventually in the occurrence of inflammation and thus produce inflammatory cytokines such as IL-1, TNF-α, IL-6, and IL-8. However, the mechanism by which the upregulation of RIP 1 induced by UVB contributes to photodamage is still unclear. AIMS:To explore the role of RIP1 in UVB-induced skin inflammation and the related signal pathways and molecular mechanism, thus providing possible molecular markers for the diagnosis and prevention of skin photodamage. METHODS:Human dermal fibroblasts were cultured in vitro from normal human skin tissues. Besides, HaCaT cell lines and Balb/c nude mice were also the research objects. First, cellular models of UVB-induced upregulation of RIP1 were established. Then, the expression of RIP1 and localization of RIP1 before and after UVB irradiation of the cells were studied through western blot and immunofluorescence. Then, the change in the expression of the nuclear factor (NF)-kappaB (NF-κB) pathway, along with RIP1 in these cells before and after UVB irradiation was detected, including NF-κB p50/p65, p-p65, IκB and cytokines such as IL-1, IL-6, IL-8, and TNF-α. Next, the effects of the RIP1 inhibitor Nec-1 and RIP1 siRNA on the expression of RIP1, p-RIP1, NF-κB p50/p65, inflammatory cytokines, and nuclear translocation of p-p65 in vitro cells after UVB irradiation were explored. At last, the expression of RIP1 and NF-κB pathway-related proteins such as p65/p50 was detected by western blot and immunohistochemistry before and after UVB radiation with or without subcutaneous injection of Nec-1 in the Balb/c nude mice were detected. RESULT:We provide that RIP1 involved in the photodamage of human dermal fibroblasts, HaCaT cell lines, and the skin tissues of Balb/c nude mice induced by UVB. Upregulated RIP1 induced by UVB ultimately upregulates inflammatory cytokines, including IL-1, IL-6, IL-8, and TNF-α by triggering the expression of NF-κB p65/p50 and activating nuclear translocation of p-p65 in cells. RIP1 inhibitor Nec-1 or RIP1 siRNA can inhibit the function of RIP1. We first illustrate that the upregulated RIP1 induced by UVB contributes to photodamage of the skin via the NF-κB signaling pathway in vivo and in vitro. CONCLUSION:The study reveals the molecular mechanism by which upregulated RIP induced by UVB contributes to the occurrence of inflammation of the skin and also provides possible molecular markers for the diagnosis and prevention of skin photodamage.

Moonlighting enzymes are multifunctional proteins that perform multiple functions beyond their primary role as catalytic enzymes. Extensive research and clinical practice have demonstrated their pivotal roles in the development and progression of cancer, making them promising targets for drug development. This article delves into multiple notable moonlighting enzymes, including GSK-3, GAPDH, and ENO1, and with a particular emphasis on an enigmatic phosphatase, PTP4A3. We scrutinize their distinct roles in cancer and the mechanisms that dictate their ability to switch roles. Lastly, we discuss the potential of an innovative approach to develop drugs targeting these moonlighting enzymes: target protein degradation. This strategy holds promise for effectively tackling moonlighting enzymes in the context of cancer therapy.

Background:Previous research has found a link between the temperature of food and beverages and the risk of esophageal cancer (EC). A causal relationship between the two has not been well established. Herein, we used Mendelian randomization (MR) analysis to assess the causal effect of temperature preference for hot beverages on EC risk. Methods:Genome-wide association studies (GWAS) data for hot beverage temperature preference were obtained from the UK biobank. There were 457,873 European and 2,617 East Asian participants included. GWAS data for EC were obtained from the Integrative Epidemiology Unit (IEU) project database. Two datasets from the European population and two datasets from the East Asian population were included. Totally, 4,426 EC cases and 1,202,270 control subjects were included. The "TwoSampleMR" R package was used to conduct a two-sample MR analysis. A random-effect inverse variance weighted (IVW) was used as the main analytical method to estimate the causal effect, and various sensitivity analyses, including MR Egger, weighted median, simple mode, and weighted mode, were used to examine the potential violation of the second and third MR assumptions. Meta-analyses were performed to further confirm the results. Results:Sixty-eight single nucleotide polymorphisms (SNPs) from the European population and 11 SNPs from the East Asian population were used for MR analysis. No significant causal effect was found between hot beverage temperature preference and EC risk in the European population {for the ieu-b-4960 dataset, inverse variance weighted odds ratio (ORIVW) =1.00 [95% confidence interval (CI): 0.99-1.00], P=0.54; for the ebi-a-GCST90018841 dataset, ORIVW =0.35 (95% CI: 0.10-1.29), P=0.12} or in the East Asian population [for the bbj-a-117 dataset, ORIVW =1.09 (95% CI: 0.80-1.48), P=0.59; for the ebi-a-GCST90018621 dataset, ORIVW =0.11 (95% CI: 0.82-1.50), P=0.49]. Meta-analyses of the European population datasets and the Asian population datasets showed consistent results. Conclusions:The current MR analysis provides new genetic evidence for a null causal relationship between hot beverage temperature preference and EC, both in the European population and the East Asian population. Evidence to prevent EC by reducing the intake of hot beverages is insufficient.

The fatty acid -binding protein 1 (FABP1) is a fatty acid transporter protein that is considered as an emerging target for metabolic diseases. Despite forceful evidence that the inhibition of FABP1 is essential for ameliorating NASH, pharmacological control and validation of FABP1 are hindered by a lack of relevant inhibitors as pharmacological tool. Therefore, the development of effective FABP1 inhibitors is a current focus of research. Herein, we firstly reported the comprehensive structure -activity relationship (SAR) study of novel FABP1 inhibitors derived from high throughput screening of our in-house library, which resulting in the identification of the optimal compound 44 (IC 50 = 4.46 +/- 0.54 mu M). Molecular docking studies revealed that 44 forms stable hydrogen bonds with amino acids around the active pocket of FABP1. Moreover, 44 alleviated the typical histological features of fatty liver in NASH mice, including steatosis, lobular inflammation, ballooning and fibrosis. Additionally, 44 has been demonstrated to have lipid metabolism regulating, anti -oxidative stress and hepatoprotective properties. This study might be provided a promising insight into the field of NASH and inspiration for the development of FABP1 inhibitors.

Objective: The objective of this study was to conduct a comprehensive pan-cancer analysis of Protein tyrosine phosphatase 4A (PTP4As), specifically PTP4A1, PTP4A2, and PTP4A3, to investigate their aberrant expression, genomic alterations, prognostic values, and molecular functions. The aim was to evaluate the roles of PTP4As in cancer development and progression, as previous research has primarily focused on PTP4A3 and yielded inconsistent results regarding their expression in cancers. Methods: A meticulous and extensive analysis of PTP4As was performed across diverse cancer types. mRNA expression levels of PTP4A isoforms were examined, and correlations between protein expression and mRNA expression were investigated. Genomic alterations affecting PTP4As, such as amplification, were analyzed. Survival analysis was conducted to assess the prognostic values of PTP4As in different cancers. Additionally, pathway enrichment analysis was performed to identify signaling pathways and biological processes associated with PTP4A2 and PTP4A3. Results: The analysis revealed that PTP4A3 exhibited the most prevalent up-regulation at the mRNA level among the PTP4A isoforms. PTP4A2 mRNA expression in cancer generally displayed an up-regulated trend. However, inconsistent results were observed for PTP4A1 expression, even within the same cancer type but across different datasets, indicating the need for further investigation. The correlation between PTP4As protein expression and mRNA expression was found to be weak, indicating the complexity of their regulatory mechanisms. Genomic analysis showed that amplification was the major type of alteration affecting PTP4As, although it did not always translate into higher expression. Survival analysis revealed that high PTP4As expression was typically associated with unfavorable prognoses in several cancers, although exceptions existed. Pathway enrichment analysis unveiled novel signaling pathways and biological processes potentially influenced by PTP4As. Conclusion: The pan-cancer analysis of PTP4As provided insights into their aberrant expression, genomic alterations, prognostic values, and molecular functions. PTP4A3 exhibited the most prevalent up-regulation, while PTP4A2 showed a general up-regulated trend. Inconsistent results were observed for PTP4A1 expression, warranting further investigation. These findings contribute to our understanding of the molecular mechanisms through which PTP4As may contribute to cancer pathogenesis.

Objectives Acute myeloid leukemia (AML) is a hematological malignancy with highly clinical heterogeneity resulting in poor outcomes. We aim to identify novel prognostic lncRNA in AML expecting to provide new clues for therapy in AML. Methods Three cohorts were enrolled in this study. Differentially expressed lncRNAs between TCGA-AML cohort and GTEx cohort was identified by DESeq2. The relationship between expression level of LOC644135 and prognosis in AML was analyzed by multiple methods. Results Pan-cancer analysis indicated that LOC644135 was most highly expressed in AML across 33 types of cancer. Patients with high expression of LOC644135 had poor overall prognosis in both TCGA-AML cohort and the TARGET-AML cohort. Especially, high expression of LOC644135 indicated inferior overall survival and event-free survival in CN-AML patients in the TCGA-AML cohort. Besides, CN-AML patients had higher expression of LOC644135 than normal samples. Multivariable analysis suggested that LOC644135 was an independent prognostic factor in AML. GSEA analysis showed that LOC644135 was associated with some immune-related pathways. Besides, high expression of LOC644135 was associated with less infiltration of CD8(+) T cell. Conclusion Our findings indicated that LOC644135 was an independent prognostic factor in AML and provided a new idea in the development of therapy in AML.

Objectives Acute myeloid leukemia (AML) is a common hematologic malignancy with high heterogeneity and poor prognosis. Although long non-coding RNAs (lncRNAs) have been used as biomarkers for tumors, the clinical relevance of numerous lncRNAs in AML remains to be investigated. Research design and methods Differentially expressed lncRNAs between AML and normal peripheral blood samples were identified using DESeq2. Pan-cancer analysis was performed by GEPIA tool. Kaplan-Meier survival curve was applied for prognosis analysis. KEGG pathway analysis and GSEA were used for functional enrichment. The ceRNA network was constructed by GDCRNAtools. Results Lnc-SMIM20-1 was most highly expressed in AML and up-regulated in the TCGA-AML cohort compared to normal tissues. Patients with high expression of Lnc-SMIM20-1 had poor overall prognosis both in the TCGA adult AML cohort and the TARGET pediatric AML cohort, no matter whether they were treated with chemotherapy or allo-HSCT. Lnc-SMIM20-1 might participate in cancer-associated signaling pathways and immune-related signaling pathways by interacting with four microRNAs and 20 mRNAs. Conclusion Lnc-SMIM20-1 was up-regulated in AML acting as a stable poor prognostic factor. The prognostic impact of Lnc-SMIM20-1 cannot be overcome by allo-HSCT. Our findings provide insight into the clinical relevance of Lnc-SMIM20-1 in AML; aiming to progress the development of novel therapeutics.

Background: Guanylate cyclase 1 soluble subunit alpha 2 (sGCα2), also known as GUCY1A2, was reported to be upregulated and promoted tumorigenesis in some cancers. But whether GUCY1A2 was abnormally expressed and the prognostic value in gastric cancer was unknown. The current study aimed to find out the prognostic value of GUCY1A2 in gastric cancer by analyzing data from The Cancer Genome Atlas (TCGA). Methods: Wilcoxon signed-rank test, cox regression analysis and multivariant analysis were used to analyze the relationship between clinical characteristic and GUCY1A2 expression level. Kaplan-Meier method was used to analyze the association of GUCY1A2 and overall survival. Gene set enrichment analysis (GSEA) was used to identify GUCY1A2-related signaling pathway. Results: Compared to normal tissue, expression of GUCY1A2 was significantly increased in gastric cancer (p=0.000). Increased GUCY1A2 was associated with advance T stage (p=0.012) and poor survival (p=0.022). Univariate analysis showed that high GUCY1A2 expression was associated with a poor overall survival (HR:1.44, 95% confidence interval [CI]: 1.03-2.02, p=0.03). Multivariate analysis indicated that GUCY1A3 remained an independent prognostic predictor of overall survival (HR:1.75, 95% confidence interval [CI]: 1.20-2.56, p=0.00). GSEA revealed that calcium signaling pathway, MAPK signaling pathway, TGF-β signaling pathway and Wnt signaling pathway were enriched in GUCY1A2 high expression phenotype. Conclusions: GUCY1A2 maybe a potential prognostic predictor of poor survival in gastric cancer. Calcium signaling pathway, MAPK signaling pathway, TGF-β signaling pathway and Wnt signaling pathway may be the key signaling pathway regulated by GUCY1A2.

To analyze the outcomes and adverse events of patients with esophageal squamous cell carcinoma (ESCC) treated with definitive chemoradiation with modified radiotherapy volume and increased radiation dose. This was a retrospective analysis of patients with ESCC treated with definitive chemoradiotherapy at the Sun Yat-sen University Cancer Center (02/2015 to 02/2017). The dose to the planning gross tumor volume (PGTV) and planning clinical tumor volume (PTV1) was 66-68 Gy (2.0-2.2 Gy/fraction). The dose to the planning regional lymph node drainage area volume (PTV2) was 46 Gy (2.0 Gy/fraction). Treatment response, adverse events, progression-free survival (PFS), overall survival (OS), and locoregional failure-free survival (LRFFS) were analyzed. Twenty-six patients were included. The median follow-up was 31 (range, 4.3-51.3) months. Sixteen (61.5%) patients had a complete response, and four (15.4%) achieved a partial response. The objective response rate was 76.9%, and the disease control rate was 80.8%. The median PFS and OS were not achieved. The 4-year PFS was 63.9%, and the 4-year OS was 71.0%. Grade 1-2 and 3-4 radiation-related esophagitis was observed in 15 (57.7%) and one (4.5%) patients, respectively. Grade 1-2 and 3-4 radiation-related pneumonitis was observed in 12 (46.2%) and one (4.5%) patients, respectively. No patients developed radiation-related heart or skin damage. The modified target volume definition and increased dose of definitive radiotherapy combined with chemotherapy in patients with ESCC had low toxicity and might improve survival, but additional trials are necessary to prove the superiority of this strategy.

The human HSP70 family is a type of heat shock protein (HSP), consisting of 13 members encoded by the HSPA genes. HSPs play important roles in regulating cellular responses and functions during carcinogenesis, but their relationship with colon cancer is unclear. In our study, we found that the expressions of HSPA1B, HSPA4, HSPA5, HSPA6, HSPA8, HSPA9, HSPA13, and HSPA14 were significantly increased, while those of HSPA1A, HSPA2, HSPA7, and HSPA12B were significantly decreased in colon cancer tissues. The expression of HSPA gene family members was associated with some clinicopathological characteristics, including age, gender, TNM stage, pathological stage, and CEA level. Furthermore, the Kaplan–Meier method and Cox regression analysis showed that high HSPA1A, HSPA1B, and HSPA7 expressions were related to unfavorable survival, and high HSPA9 was associated with favorable survival. The relationships between HSPA1A and HSPA9 expression and survival were validated in the GEO dataset, and the HSPA1A and HSPA9 protein expression differences between colon cancer tissues and normal tissues were validated in the UALCAN database. Methylation of HSPA1A and HSPA9 was also analyzed, and it was found that the methylation of the HSPA1A promoter was significantly increased, and the methylation of the HSPA9 promoter was significantly decreased in colon cancer tissues. Increasing the methylation level of the HSPA1A gene and decreasing the methylation level of HSPA9 were related to favorable prognosis. The expression difference of HSPA1A/HSPA1B/HSPA7/HSPA9 was verified in colon cancer cell lines and colonic epithelial cells. Gene ontology analysis was used to screen signal pathways related to HSPA1A-, HSPA1B-, HSPA7-, and HSPA9- high phenotype. In summary, the increased expressions of HSPA1A1, HSPA1B, and HSPA7 were associated with poor prognosis, while that of HSPA9 was related to favorable prognosis for colon cancer patients.

Purpose: TNBC with germline BRCA1/2 mutation (gBRCAm) have higher sensitivity to DNA damaging agents including platinum-based chemotherapy and PARP inhibitors. But the treatment of TNBC without gBRCAm remains challenging. This study aimed to develop a long non-coding RNA (lncRNA) signature of TNBC patients without gBRCAm to improve risk stratification and optimize individualized treatment. Methods: 98 TNBC patients without gBRCAm were acquired from The Cancer Genome Atlas database. The univariable Cox regression analysis and LASSO Cox regression model were applied to establish an lncRNA signature in the training cohort. Then Kaplan–Meier survival curve and time-dependent ROC curve were used to validate the prognostic ability of the signature. The qPCR assay was performed to confirm the expressions and clinicopathological correlations of two potential lncRNAs HAGLROS and TONSL-AS1 in 30 paired clinical triple-negative breast cancer samples without gBRCAm. Results: We developed an 8-lncRNA signature in the training cohort including HAGLROS, AL139002.1, AL391244.2, AP000696.1, AL391056.1, AL513304.1, TONSL-AS1 and AL031008.1. Patients with higher risk scores showed significantly worse overall survival compared to those with lower risk scores (P=0.00018 and P =0.0068 respectively). 30 paired specimens of TNBC without gBRCAm in our center showed that two potential lncRNAs HAGLROS and TONSL-AS1 were found frequently overexpressed, and significantly associated with tumor grade and invasion. Conclusion: We constructed a novel 8-lncRNA signature which significantly associated with the overall survival of TNBC patients without gBRCAm. Among those 8 lncRNAs, HAGLROS and TONSL-AS1 may be potential therapeutic targets which function needed further exploration.

Purpose:To assess the survival outcomes of patients with metastatic prostate cancer (mPCa) who undergo greater cytoreductive radiotherapy in a real-world clinical practice and determine their prognostic factors. Methods:We performed a retrospective study of 160 patients with mPCa who underwent cytoreductive radiotherapy between 2009 and 2018 at a single institution. The degree of the cytoreductive burden was calculated for each patient. Overall survival (OS) was calculated from the date of detection of metastases. Variables associated with prostate-specific antigen (PSA) response and OS were evaluated via univariate and multivariate analyses. Results:The median follow-up period was 47.2 months. The median OS was 42.3 months with a 5-year OS rate of 37.9%. The PSA levels of 90 patients (56.7%) decline by > 50% after radiotherapy. The 5-year OS rates of patients who underwent total, major, and minor cytoreductive radiotherapy were 53.4, 38.2, 17.6%, respectively; the corresponding median OS intervals were 62.5, 41.0, and 24.4 months, respectively (P< 0.001). A greater extent of cytoreduction (P< 0.05), lower PSA at radiotherapy initiation [hazard ratio 0.51, 95% confidence interval [CI] 0.33-0.78;P= 0.002] and better PSA response [hazard ratio 0.47, 95% CI 0.30-0.72;P< 0.001] were independent factors associated with superior OS. A high metastatic burden (as defined in the CHAARTED trial) was the only independent predictor of a poorer PSA response (odds ratio 0.36, 95% CI 0.19-0.69;P= 0.002). Grade 2 late gastrointestinal and genitourinary toxicities were observed in 3 and 2 patients, respectively, and only 1 patient had grade 3 late gastrointestinal toxicity. Conclusion:Cytoreductive radiotherapy is effective and safe in select patients with mPCa. Greater cytoreduction, together with lower PSA at radiotherapy initiation and improved PSA response are favorable prognostic factors. Further studies are needed to confirm our findings.

The tyrosine protein tyrosine phosphatase PTP4A3 has been extensively reported to play a causative role in numerous cancers, including several types of acute leukemia. We found PTP4A3 to be highly expressed in T-cell Acute Lymphoblastic Leukemia samples, and show that PTP4A3 accelerates T-ALL onset and increases the invasive ability of T-ALL cells in a zebrafish model, and is required for T-ALL engraftment and progression in mouse xenograft. Our in vitro studies showed that PTP43A3 enhances T-ALL migration, in part via modulation of SRC signaling. However, whether SRC is a direct substrate of PTP4A3, and whether the phosphatase activity of PTP4A3 actually plays a role in T-ALL or other types of leukemia progression is unknown and remains a major question in the field. We used a BioID-based proximity labeling approach combined with PTP4A3 substrate trapping mutant pull down assay to capture the PTP4A3 substrates candidates. BioID, a biotin ligase, was fused to PTP4A3 to generate a Biotin-PTP4A3 (BP) fusion protein. The overexpression of BP in T-ALL cell lines led to biotin modification of 288 PTP4A3 proximal proteins, including the potential direct PTP4A3 substrates. PANTHER pathway analysis showed that PTP4A3 interacting proteins are largely clustered in the T-cell activation, PDGF signaling, and angiogenesis. We are in process of validating potential substrates using immunoprecipitation and phosphoenrichement assays. Finally, we are using a novel zebrafish Myc+PTP4A3 induced T-ALL model to assess the function of PTP4A3 in leukemia progression. We have created several PTP4A3 protein mutants, including a phosphatase-dead mutant, a mutant unable to bind magnesium transporter, and a prenylation deficient mutant, and are in process of assessing the effects of these mutants in T-ALL onset and progression in our in vivo model. In total, these studies will allow us to better understand function of PTP4A3 in T-ALL progression, and may provide a strong rationale for the development of PTP4A3 inhibitors for use in leukemia. Disclosures No relevant conflicts of interest to declare.