Matrine exerts an anti-tumor effect via regulating HN1 in triple breast cancer both in vitro and in vivo.

The treatment of triple-negative breast cancer (TNBC) cannot meet medical needs, and it is urgent to find new drugs for intervention. This study aimed to investigate the anti-tumor effect of matrine on the proliferation and apoptosis of TNBC cells based on HN1 regulation in vitro and in vivo. TNBC cell lines (MDA-MB-453 and HCC-1806) were treated with varying concentrations of matrine (0, 1.0, 2.0, 3.0, 4.0, and 5.0 mM). CCK-8, colony formation assay, transwell assay, and flow cytometry assay were employed to detect proliferation, clone formation, invasion, and apoptosis of TNBC cells. Western blot analysis was applied to detect the protein expression of apoptosis HN1. The effects of matrine on tumor growth, protein expression of HN1, and apoptosis in vivo were validated by xenograft tumor models and histology. It was found that matrine inhibited proliferation, colony formation, and invasion and promoted apoptosis of TNBC cells in vitro. HN1 expression was suppressed by matrine. HN1 overexpression perceptibly reversed the above-mentioned additive effect in vitro. In vivo experiments found that matrine inhibited tumor growth and the expression of HN1 protein but promoted the protein expression of Cleared-Caspase-3. Above all, this study demonstrated that matrine inhibited proliferation and promoted apoptosis of TNBC cells via suppressing HN1 expression. Targeting HN1 by matrine may provide new insights into the therapeutic management of patients with TNBC.

Higher Levels of Tumour-Infiltrating Lymphocytes (TILs) are Associated with a Better Prognosis, While CDK5 Plays a Different Role Between Nonmetastatic and Metastatic Colonic Carcinoma.

OBJECTIVE: We investigated the prognostic value of cyclin-dependent kinase 5 (CDK5) in a true population-based cohort of patients with colon cancer. METHODS: 1. Immunohistochemical (IHC) staining was used to retrospectively analyse the expression of CDK5 in colon cancer tissue samples of 296 patients. The χ2 test, Kaplan-Meier method and Cox proportional regression model were used to analyse the difference between the patients with differential expression of CDK5 and with different stages (metastatic and nonmetastatic); 2. The number of tumour-infiltrating lymphocytes (TILs) in tumour sections was determined, and its relationship with prognosis was explored. RESULTS: 1. Among 296 patients stained for CDK5, 18 cases (6.09%) showed negative expression, 77 cases (26.01%) showed weak expression (+1), 124 cases (41.89%) showed medium positive expression (2+), and 77 cases (26.01%) showed strong positive expression (3+). The expression of CDK5 was neither related to mismatch repair nor TILs (p > .05). In non-metastatic patients, longer progression-free survival (PFS) and cancer-specific survival (CSS) were observed in patients with high CDK5 expression (2+ or 3+) than low CDK5 expression (- or 1+), while in metastatic disease, the opposite was true (p < .001). 2. TILs in 226 patients were detected in the study. Among them, 115 cases (50.88%) showed a low number of TILs (TILs-L), and 111 cases (49.12%) showed a high number of TILs (TILs-H). Patients with a TIL ratio greater than .2 had a significantly better CSS (p < .001) or PFS (p = .008) than patients with a lower TIL ratio. By multivariate analysis, TILs-H was a protective factor for CSS, however failed to reach a significant difference (hazard ratio: .59, 95% CI: .33∼1.06, p = .079), and so was the PFS (HR: .65, 95% CI: .29∼1.43, p = .279). CONCLUSION: High expression of CDK5 indicates a good prognosis in nonmetastatic colon cancer, while it is the opposite in metastatic colon cancer, and the expression of CDK5 is unrelated to TILs. Patients with TIL-H have a better prognosis, with a proper cut-off value of 20% for colon cancer.

The predictive model for risk of chemotherapy-induced thrombocytopenia based on antineoplastic drugs for solid tumors in eastern China.

Chemotherapy-related thrombocytopenia (CIT) is a significant adverse event during chemotherapy, which can lead to reduced relative dose intensity, increased risk of serious bleeding and additional medical expenditure. Herein, we aimed to develop and validate a predictive nomogram model for prediction of CIT in patients with solid tumor. From Jun 1, 2018 to Sep 9, 2021, a total of 1541 patients who received 5750 cycles of chemotherapy were retrospectively enrolled. Cox regression analysis was performed to identify predictive factors to establish the nomogram model for CIT. The incidence of chemotherapy-induced thrombocytopenia was 21.03% for patient-based and 10.26% for cycles of chemotherapy. The top five solid tumors with CIT are cervix, gastric, bladder, biliary systemic, and ovarian. The incidence of chemotherapy dose delays in any cycle because of CIT was 5.39%. Multivariate analysis showed that tumor site, treatment line, AST, oxaliplatin, and capecitabine were significantly associated with CIT. Moreover, we established a nomogram model for CIT probability prediction, and the model was well calibrated (Hosme-Lemeshow P = 0.230) and the area under the receiver operating characteristic curve was 0.844 (Sensitivity was 0.625, Specificity was 0.901). We developed a predictive model for chemotherapy-induced thrombocytopenia based on readily available and easily assessable clinical characteristics. The predictive model based on clinical and laboratory indices represents a promising tool in the prediction of CIT, which might complement the clinical management of thrombocytopenia.

The impact of age on outcomes of breast cancer in different hormone receptor and HER2 groups.

OBJECTIVE: The aim of the current study was to explore the association between age and outcomes in breast cancer. METHODS: Patients during 2010-2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and breast cancer-specific death (BCSD) were taken as endpoints. The restrict cubic spline graph (RCS) was used to explore the relationship between age and outcomes in patients, and the cumulative incidence of BCSD and non-BCSD was calculated using the Gray method. Age-specific gene expression profiles were studied using RNA sequence data from the Cancer Genome Atlas (TCGA) database to explore whether there were young age-related gene or gene sets. RESULTS: A total of 142,755 patients with breast cancer were included. The hazard ratio (HR) of OS for Patients with stage I-III breast cancer was roughly stable before 53 years old and increased significantly after that, and the HR of BCSD for these patients showed a U-shaped distribution when plotted against age, with patients younger than 50 years and patients older than 70 years experiencing the worst survival. Further stratified analysis according to molecular subtype revealed that the U-shaped distribution of the HR of BCSD with was only found in the Hormone receptor-positive/HER2-negative (HoR+/HER2-) subgroup. The cumulative incidence plots showed that young age was associated with worse BCSD in the breast cancer patients with stage I-III and HoR+/HER2- subgroup. In stage IV breast cancer, there was a linearity of the relationship between poor OS and increasing age. We failed to find any differentially expressed age-specific genes between 20-40 years and 41-60 years groups in 258 patients with stage I-III and HoR+/HER2- subtype. CONCLUSION: Young age could predict worse BCSD of patient with stage I-III and HoR+/HER2- breast cancer. The escalating therapy was recommended to young age breast cancer with stage I-III and HoR+/HER2- subtype.

Resection of primary lesion with chemotherapy improves the survival of patients with metastatic colorectal neuroendocrine carcinoma.

OBJECTIVE: To evaluate the effect of resection of primary lesion and chemotherapy on survival of patients with metastatic colorectal neuroendocrine carcinoma (CRNEC). METHODS: Clinical data of 393 patients with metastatic CRNECs between January 2010 and December 2016 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database, including 171 patients who received resection of primary lesion and 221 patients who did not undergo surgery. With the propensity score matching method 172 non-operated patients were selected as controls. Kaplan-Meier method and Log-rank test were used to evaluate the survival differences, while the prognostic factors were analyzed by Cox proportional-hazards model. Metastatic CRNEC patients from January 2001 to December 2021 in Affiliated Jinhua Hospital, Zhejiang University School of Medicine were selected for validation. RESULTS: Compared with non-operated patients, patients who received resection had longer cause-specific survival ( P<0.05). Patients with resected positive lymph nodes>8 had a poorer prognosis compared to those with resected positive lymph nodes≤8 ( P<0.05). Multivariate analysis showed that gender, location of primary lesion and treatments were independent risk factors for cause-specific survival in patients with metastatic CRNEC (all P<0.05). For metastatic CRNEC patients with resection of primary lesion, rectal neuroendocrine carcinoma, positive resected lymph nodes≤8 and resection of primary lesion combined with chemotherapy were associated with better cause-specific survival (all P<0.05). CONCLUSIONS: Patients with metastatic CRNEC may benefit from resection of primary lesion, and resection of primary lesion combined with chemotherapy might be the better strategy for metastatic CRNECs. The number of positive lymph nodes resected is correlated with the prognosis of patients.

Estrogen receptor-negative/progesterone receptor-positive and her-2-negative breast cancer might no longer be classified as hormone receptor-positive breast cancer.

BACKGROUND: The single progesterone receptor (PR)-positive phenotype (estrogen receptor (ER)-/PR + , sPR positive) is an infrequent and independent biological entity. However, the prognosis of patients with sPR-positive and her-2-negative phenotype is still controversial, and it is not always easy to decide treatment strategies for them. METHODS: Patients during 2010-2014 were identified from Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method was used to evaluate cancer-specific survival (CSS). The propensity score matching (PSM) method was used to balance differences of characteristics in groups. The Life-Table method was used to calculate 5-year CSS rates and the annual hazard rate of death (HRD). RESULTS: A total of 97,527 patients were included, and only 745 (0.76%) patients were sPR-positive phenotype. The majority of sPR-positive breast cancer were basal-like subtype. Survival analysis showed that the sPR-positive breast cancer had similar prognosis comparing to double hormonal receptor-negative (ER-/PR-, dHoR-negative) breast cancer, and had the highest HRD during the initial 1-2 years of follow-up, then maintained the HRD of almost zero during the late years of follow-up. CONCLUSIONS: The patients with sPR-positive and her-2-negative breast cancer, similar to dHoR-negative breast cancer, had a worse survival, and could benefit from chemotherapy significantly. However, the escalating endocrine therapy was not recommended for sPR-positive patients. The patients with sPR positive should be excluded from future clinical trials concerning endocrine therapy.

Competing Nomogram for Late-Period Breast Cancer-Specific Death in Patients with Early-Stage Hormone Receptor-Positive Breast Cancer.

BACKGROUND: More than half of early breast cancer recurrences occur after 5 years from the initial diagnosis. An individualized estimate of the risk of late-period breast cancer-specific death (LP-BCSD) after 5 years of endocrine therapy (ET) can improve decision-making for extended endocrine therapy (EET). MATERIALS AND METHODS: A total of 147,059 eligible patients with breast cancer who survived 5+ years after diagnosis between 1990 and 2007 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses based on the competing risk regression model were used to evaluate predictive factors for high risk of LP-BCSD or late-period non-breast cancer-specific death (LP-non-BCSD). Significant factors were used to build a nomogram to individualize estimates of LP-BCSD or LP-non-BCSD. RESULTS: The 5- and 10-year LP-BCSD rates were 5.7% and 10.1%, respectively, and the 5- and 10-year LP-non-BCSD rates were 6.7% and 15.5%, respectively. Young age, black race, single marital status, poor differentiation, large tumor size, lymph node metastasis, and estrogen receptor-positive/progesterone receptor-negative (ER+/PR-) status were independent predictive factors for high risk of LP-BCSD. Age was the most important factor for predicting high risk of LP-non-BCSD. The nomograms, which were based on significant factors identified by the competing risk regression model. A risk score system based on the competing risk nomogram was established to describe the relative risk of LP-BCSD and LP-non-BCSD. CONCLUSION: This study explored the novel endpoint of LP-BCSD for further clinical trials. The risk score system might be highly useful for patient counseling, especially in discussing EET options with elderly or comorbid patients.

A Case Report: Cutaneous Metastasis of Advanced Rectal Cancer with BRAF Mutation.

Cutaneous metastasis of rectal cancer is rare and typically indicates widespread disease and poor prognosis. We report an exceedingly rare case of BRAF-mutated MSS rectal cancer with metastasis to the skin. A 53-year-old woman presented with stage IV unresectable adenocarcinoma of the rectum and received chemotherapy and molecularly targeted agents. Six months later she developed a focal skin nodule in the left groin. During treatment with four cycles of FOLFIRI plus bevacizumab, the skin nodules gradually increased in size, involving the skin of the left thigh. A portion of the rash was bleeding and painful. The biopsy specimen was consistent with a mucinous adenocarcinoma of rectal origin and expressed reduced CDX-2. Palliative treatment with FOLFIRI plus cetuximab and vemurafenib was initiated. The cutaneous nodules decreased in size but were not stable. The patient had severe electrolyte disturbances and depression and opted for palliative care.

The Effect of Adjuvant Treatment in Small Node-negative HER2-positive Breast Cancer: Which Subgroup Will Benefit?

BACKGROUND: We conducted this study to evaluate whether patients with T1a/b, node-negative (N-), human epidermal growth factor receptor 2-positive (HER2+) breast cancers benefited from adjuvant therapy, and explored better treatment strategies for these patients. PATIENTS AND METHODS: Patients with T1a/b, N-, HER2+ breast cancers during 2000 through 2004 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The Gray test was used to evaluate breast cancer-specific death (BCSD) and non-BCSD. To identify patients more suitable for chemotherapy, subgroup analyses were conducted according to tumor size and estrogen receptor (ER) status, and plots of hazard rate of death (HRD) were drawn to present the changes of BCSD. RESULTS: A total of 2940 patients with T1a/b, N-, HER2+ breast cancers were included; more patients in the T1b group received chemotherapy compared with the T1a group (65.18% vs. 29.30%; P < .001). Patients receiving chemotherapy did not benefit from it (5-year incidences of BCSD: 1.00% in the non-chemotherapy group vs. 1.18% in the chemotherapy group; P = .853). Compared with those in the T1a group, patients in the T1b group had similar prognosis (P = .532), whereas ER status was significantly associated with survival (P = .048). HRD had a peak in years 2 to 5, which was more obvious in the ER- group. CONCLUSION: Chemotherapy, which is mainly decided by tumor size, fails to render survival benefits for patients with T1a/b, N-, HER2+ breast cancers. ER status, rather than tumor size, is important for clinicians to make adjuvant treatment decisions. The peak of BCSD occurs 2 to 5 years after diagnosis, and an at least 5-year follow-up is recommended for these patients.

Inhibition of Serine Metabolism Promotes Resistance to Cisplatin in Gastric Cancer.

BACKGROUND: Serine provides important precursors of protein, lipid, and nucleotide synthesis needed for tumor cell growth. Phosphoglycerate dehydrogenase (PHGDH), a key rate-limiting enzyme in the serine de novo synthesis pathway, is highly expressed in many tumor types (including gastric cancer) and negatively correlated with overall survival. Cisplatin is a chemotherapeutic drug commonly used in the treatment of gastric cancer. In this study, we mainly investigated the relationship between serine metabolism and resistance to cisplatin in gastric cancer cells, as well as the regulatory mechanism involved in this process. MATERIALS AND METHODS: We determined the effect of different concentrations of serine or a PHGDH inhibitor combined with cisplatin or oxaliplatin on the viability and apoptosis of SGC7901, BGC823, and MGC803 cells via the Cell Counting Kit-8 and Hoechst 33258 staining, respectively. Western blotting was utilized to detect the relative protein expression. Furthermore, we investigated DNA damage through the micrococcal nuclease sensitivity assay detected using agarose gels. RESULTS: We found that reduced concentrations of serine or inhibition of PHGDH hindered the toxicity and pro-apoptotic effects of cisplatin on gastric cancer cells. Moreover, the addition of serine could reverse the sensitivity of gastric cancer cells to cisplatin. Moreover, we found that DNA damage was reduced by treatment with PHGDH inhibitor NCT-503 or CBR-5884. Inhibition of serine metabolism induced a decrease in H3K4 tri-methylation, which was reversed by JIB-04 (inhibitor of H3K4 demethylase). The tolerance of gastric cancer cells to cisplatin was relieved by JIB-04. Through micrococcal nuclease experiments, we further found that inhibiting the activity of PHGDH strengthened chromatin tightness. CONCLUSION: Inhibition of serine metabolism reduced H3K4 tri-methylation and increased the density of chromatin, which leads to decreased toxicity and pro-apoptotic effect of platinum chemotherapeutic drugs on gastric cancer cells.

p.L105Vfs mutation in a family with thymic neuroendocrine tumor combined with MEN1: a case report.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder arising from mutations of the MEN1 tumor suppressor gene on chromosome 11q13; MEN1 is characterized by the development of neuroendocrine tumors, including those of the parathyroid, gastrointestinal endocrine tissue and anterior pituitary. Additionally, thymic neuroendocrine tumors in MEN1 are also rarely reported. CASE PRESENTATION: This case report observed a family that presented with MEN1 p.L105Vfs mutation, and two of the family members had been diagnosed with thymic neuroendocrine tumor combined with MEN1. To the best of our knowledge, this is the first time such a mutation in the MEN1 gene has been reported. The proband presented with thymic neuroendocrine tumor, parathyroid adenoma and rectum adenocarcinoma. The son of the proband presented with thymic neuroendocrine tumor, gastrinoma, hypophysoma and parathyroid adenoma. Genetic testing revealed the frameshift mutation p.L105Vfs, leading to the identification of one carrier in the pedigree (the patient's younger sister). The proband then underwent parathyroidectomy at the age of 26 years (in 1980) for a parathyroid adenoma. Subsequently, the patient underwent thymectomy, radiotherapy and chemotherapy. The patient is now 64 years old, still alive and still undergoing Lanreotide therapy. CONCLUSION: Thymic neuroendocrine MEN1 is rare, but it accounts for almost 20% of MEN1-associated mortality. Consequently, we should focus on regular clinical screening of the thymus in MEN1 patients.

Overexpression of GOLPH3 is associated with poor survival in Non-small-cell lung cancer.

As a highly conserved protein of the Golgi apparatus, Golgi phosphoprotein 3 (GOLPH3) has been shown to be involved in tumorigenesis. This study aims to explore the expression and significance of GOLPH3 in non-small-cell lung cancer (NSCLC). We found that GOLPH3 expression was significantly elevated in NSCLC tissues when compared with adjacent lung tissues (p<0.01). Moreover, GOLPH3 expression was significantly associated with histological type (p<0.01), differentiation (p<0.01), and lymph node metastasis (p<0.05). Kaplan-Meier survival analysis showed that overall survival of patients with high expression of GOLPH3 was significantly shorter (n=100, p<0.05). In addition, GOLPH3 knock-down in two independent NSCLC cell lines inhibited cell viability through the induction of cell cycle arrest and apoptosis. In conclusion, GOLPH3 is closely related to the progression in NSCLC and could be served as a potential prognostic biomarker and therapeutic target for NSCLC.

Regulation of CRADD-caspase 2 cascade by histone deacetylase 1 in gastric cancer.

CRADD, also referred as RAIDD, is an adaptor protein that could interact with both caspase 2 and RIP that can promote apoptosis once activated. HDAC inhibitors are promising anti-cancer agents by inducing apoptosis of various cancer cells. In this study, we found that CRADD was induced by TSA (trichostatin A) to activate caspase 2-dependent apoptosis. CRADD was downregulated in gastric cancer and the restoration of its expression suppressed the viability of gastric cancer cells. HDAC1 was responsible for its downregulation in gastric cancer since HDAC1 siRNA upregulated CRADD expression and HDAC1 directly bound to the promoter of CRADD. Therefore, the high expression of HDAC1 can downregulate CRADD to confer gastric cancer cells the resistance to caspase 2-dependent apoptosis. HDAC inhibitors, potential anti-cancer drugs under investigation, can promote caspase 2-dependent apoptosis by inducing the expression of CRADD.