Genetic variants in IL12 influence both hepatitis B virus clearance and HBV-related hepatocellular carcinoma development in a Chinese male population

Abstract

IL12 plays a major role not only in inducing appropriate immune responses against viral infections (including HBV) but also in the antitumor immune response. This study was conducted to investigate the relationships of genetic variants in IL12 with hepatitis B virus (HBV) clearance and development of HBV-related hepatocellular carcinoma (HCC). We genotyped three single nucleotide polymorphisms (SNPs) of the IL12A (rs568406 and rs2243115) and IL12B (rs3212227) in 395 HBV-positive HCC patients, 293 persistent HBV carriers and 686 subjects with HBV natural clearance from southern China, using the improved multiplex ligase detection reaction (iMLDR) method. Logistic regression analysis adjusted for age, smoking, and alcohol consumption status showed that rs568408 variant genotypes were significantly associated with host HBV-related HCC risk when compared with persistent HBV carriers, and carriers of the GA + AA genotype decreased the HCC risk in comparison with GG carriers (adjusted OR = 0.53, 95 % CI 0.35–0.80, P = 0.002). No relationships between the rs2243115 and rs3212227 SNPs and HCC risk were observed (all P > 0.05). Besides, rs568408 showed an approaching significant effect on susceptibility to HBV persistent infection (adjusted OR = 1.34, 95 % CI 0.99–1.81, P = 0.057 in dominant genetic models). Furthermore, the TG haplotype was observed to be associated with a significantly increased risk of HBV-related HCC (OR = 1.42, 95 % CI 1.10–1.83, P = 0.006), while TA haplotype was associated with a decreased risk of HBV-related HCC (OR = 0.61, 95 % CI 0.45–0.83, P = 0.002). Our results reveal that the IL12A rs568408 variant may be a marker SNP for risk of both HBV clearance and HBV-related HCC development.

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Inhibitory effects of Arhgap6 on cervical carcinoma cells

Abstract

Ras homology GTPase activation protein 6 (Arhgap6), as a member of the rhoGAP family of proteins, performs vital functions on the regulation of actin polymerization at the plasma membrane during several cellular processes. The role of Arhgap6 in the progression and development of cancer remains nearly unknown. This study aimed at exploring the effects of Arhgap6 on cervical carcinoma. Human cervical cancer cells HeLa and SiHa were transduced with a lentivirus targeting Arhgap6 (Arhgap6+), while CaSki and C4-1 cells were transfected with miRNA. Cell proliferation was identified by Cell Counting Kit-8 (CCK-8). Cell cycle distribution and cell apoptosis were identified by flow cytometry. The capacity of cell migration, invasion, and adhesion were detected by Transwell assay. Further, quantitative real-time PCR (qRT-PCR) and western blot were used to analyze the expression levels of Arhgap6 and several tumor-related genes. Co-immunoprecipitation assay was performed to validate the interaction between Arhgap6 and Rac3 (Ras-related C3 botulinum toxin substrate 3). Results showed that Arhgap6 inhibited cell proliferation, migration, invasion, and adhesion of cervical carcinoma, induced cell apoptosis, and caused cell cycle arrest in the G0/G1 phase (n = 3, p < 0.05). Expression of the tumor suppressor genes and oncogenes were up- and down-regulated respectively by Arhgap6, and Rac3 was proved to be the target of Arhgap6. Besides, in in vivo assays, tumor size and weight were destructed in Arhgap6+ athymic nude mouse. This study indicated that Arhgap6 may play a role in the treatment of cervical cancer as a tumor supressor.

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Assessing cancer-related distress in cancer patients and caregivers receiving outpatient psycho-oncological counseling

Abstract

Purpose

The diagnosis of cancer, the symptoms of the illness and its treatment have an influence on how patients and their caregivers experience distress. However, data focusing on caregivers and their cancer-related distress in the outpatient setting is sparse. This study aimed to compare cancer-related distress of caregivers and patients and to derive implications for the system of outpatient psycho-oncological care.

Methods

One hundred thirty-eight patients and 102 caregivers receiving psycho-oncological counseling completed a standardized interview based on a self-assessment questionnaire (Questionnaire on Stress in Cancer Patients, FBK).

Results

Group comparisons for cancer-related distress revealed one statistically significant difference for the subscale ‘Fear’ of the FBK, Z = 2.308, p = .021, and d = .44. Caregivers showed higher cancer-related fear (M = 2.76, SD = 1.14) than patients (M = 2.41, SD = 1.29). There were no differences in ‘psychosomatic complaints’, ‘information deficit’, ‘restrictions in everyday life’, ‘social strains’, or the total score of the FBK.

Conclusions

Caregivers seem to experience cancer-related distress equal to or even more severely than patients themselves. Results suggest that there is a need for more low-threshold offers of outpatient psycho-oncological counseling for caregivers.

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Developing and implementing a complex Complementary and Alternative (CAM) nursing intervention for breast and gynecologic cancer patients undergoing chemotherapy—report from the CONGO (complementary nursing in gynecologic oncology) study

Abstract

Purpose/objectives

The purpose of this study was to develop a complex nursing intervention including complementary and alternative medicine (CAM) for breast and gynecologic cancer patients during chemotherapy to improve quality of life.

Methods

Data sources Theoretical framework and concepts, practical nursing knowledge, and evidence-based studies were compiled in interprofessional meetings.

Data synthesis The final complex intervention consists of three autonomous, but interacting components: (1) CAM nursing package, (2) resource-oriented counseling, and (3) evidence-based information material on CAM. CAM interventions include acupressure, aromatherapy, compress, and massage, targeting 14 clinically relevant symptoms during chemotherapy. Participants receive these interventions during chemotherapy with instructions for self care. During a counseling interview, the patient’s needs and preferences are assessed by trained nurses. Furthermore, participants are equipped with evidence-based information material (booklet and DVD). Prior to study start, nurses attended training modules for administering CAM therapies and for communicating and counseling within the salutogenic approach.

Conclusions

It was possible to design a multimodal CAM nursing intervention based on a theoretical concept, evidence-based studies, and practical nursing experience targeting the prevention or relief of side-effects women suffer during chemotherapy. The systematic analysis of the CONGO study will contribute to evidence-based CAM nursing care within supportive cancer care.

Implications for integrative cancer care

Oncology nurses play an important role in supportive CAM care of breast and gynecologic cancer patients in daily clinical practice. Within oncology outpatient services, the implementation of evidence-based CAM nursing interventions and counseling may contribute to understand the impact of nursing on patient quality of life and symptom relief. This can lead to a new understanding of the nurse’s professional role.

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Penfluridol: An antipsychotic agent suppresses metastatic tumor growth in triple negative breast cancer by inhibiting integrin signaling axis

Metastasis of breast cancer, especially to the brain, is the major cause of mortality. The inability of anti-cancer agents to cross the blood-brain-barrier represents a critical challenge for successful treatment. In the current study, we investigated the anti-metastatic potential of penfluridol (PF), an antipsychotic drug frequently prescribed for schizophrenia with anti-cancer activity. We show that PF induced apoptosis and reduced the survival of several metastatic triple negative breast cancer (TNBC) cell lines. Additionally, PF treatment significantly reduced the expression of integrinα6, integrin β4, Fak, Paxillin, Rac1/2/3, and ROCK1 in vitro. We further evaluated the efficacy of PF in three different in vivo tumor models. We demonstrate that PF administration to an orthotopic model of breast cancer suppressed tumor growth by 49%. On the other hand, PF treatment inhibited the growth of metastatic brain tumors introduced by intracardiac or intracranial injection of breast cancer cells by 90% and 72%, respectively. PF-treated tumors from all three models exhibited reduced integrinβ4 and increased apoptosis. Moreover, chronic administration of PF failed to elicit significant toxic or behavioral side effects in mice. Taken together, our result indicate that PF effectively reduces the growth of primary TNBC tumors and especially metastatic growth in the brain by inhibiting integrin signaling, and prompt further preclinical investigation into repurposing PF for the treatment of metastatic TNBC.

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The CDK9 inhibitor dinaciclib exerts potent apoptotic and antitumor effects in preclinical models of MLL-rearranged acute myeloid leukemia

Translocations of the mixed lineage leukemia (MLL) gene occur in 60-80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDACs), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate protumorigenic gene expression programs. We conducted a small molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven AML. We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the pro-survival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclib-induced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies, and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins.

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Melphalan, Antimelanoma Immunity, and Inflammation—Letter

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