Loss of feedback regulation between FAM3B and androgen receptor driving prostate cancer progression.

BACKGROUND: Although the fusion of the transmembrane serine protease 2 gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2-ERG, occurs frequently in prostate cancer, its impact on clinical outcomes remains controversial. Roughly half of TMPRSS2-ERG fusions occur through intrachromosomal deletion of interstitial genes and the remainder via insertional chromosomal rearrangements. Because prostate cancers with deletion-derived TMPRSS2-ERG fusions are more aggressive than those with insertional fusions, we investigated the impact of interstitial gene loss on prostate cancer progression. METHODS: We conducted an unbiased analysis of transcriptome data from large collections of prostate cancer samples and employed diverse in vitro and in vivo models combined with genetic approaches to characterize the interstitial gene loss that imposes the most important impact on clinical outcome. RESULTS: This analysis identified FAM3B as the top-ranked interstitial gene whose loss is associated with a poor prognosis. The association between FAM3B loss and poor clinical outcome extended to fusion-negative prostate cancers where FAM3B downregulation occurred through epigenetic imprinting. Importantly, FAM3B loss drives disease progression in prostate cancer. FAM3B acts as an intermediator of a self-governing androgen receptor feedback loop. Specifically, androgen receptor upregulates FAM3B expression by binding to an intronic enhancer to induce an enhancer RNA and facilitate enhancer-promoter looping. FAM3B, in turn, attenuates androgen receptor signaling. CONCLUSION: Loss of FAM3B in prostate cancer, whether through the TMPRSS2-ERG translocation or epigenetic imprinting, causes an exit from this autoregulatory loop to unleash androgen receptor activity and prostate cancer progression. These findings establish FAM3B loss as a new driver of prostate cancer progression and support the utility of FAM3B loss as a biomarker to better define aggressive prostate cancer.

A detailed characterization of stepwise activation of the androgen receptor variant 7 in prostate cancer cells.

Expression of the androgen receptor splice variant 7 (AR-V7) is frequently detected in castrate resistant prostate cancer and associated with resistance to AR-targeted therapies. While we have previously noted that homodimerization is required for the transcriptional activity of AR-V7 and that AR-V7 can also form heterodimers with the full-length AR (AR-FL), there are still many gaps of knowledge in AR-V7 stepwise activation. In the present study, we show that neither AR-V7 homodimerization nor AR-V7/AR-FL heterodimerization requires cofactors or DNA binding. AR-V7 can enter the nucleus as a monomer and drive a transcriptional program and DNA-damage repair as a homodimer. While forming a heterodimer with AR-FL to induce nuclear localization of unliganded AR-FL, AR-V7 does not need to interact with AR-FL to drive gene transcription or DNA-damage repair in prostate cancer cells that co-express AR-V7 and AR-FL. These data indicate that AR-V7 can function independently of its interaction with AR-FL in the true castrate state or "absence of ligand", providing support for the utility of targeting AR-V7 in improving outcomes of patients with castrate resistant prostate cancer.

Clinical efficacy of anesthesia with intensive care nursing in attenuating postoperative complications in patients with breast cancer.

OBJECTIVE: Complications frequently occur in patients with breast cancer after surgery. Anesthesia nursing plays an important role in decreasing complications for such patients. Thus, this study investigated the effects of anesthesia with intensive care nursing (AICN) on complication rates in patients with breast cancer after surgery. METHODS: Eighty-two patients with breast cancer were recruited in this study. Complications were compared between the anesthesia with usual nursing care (AUCN) and AICN groups. RESULTS: The results demonstrated that AICN decreased the rates of incision infection, drug extravasation, and catheter exposure, as well as pain and inflammation scores, compared with the findings in the AUCN group. AICN improved the time to orientation and decreased the incidence of nausea, anxiety, depression, and vomiting versus AUCN. In addition, AICN shortened the time to awakening after anesthesia compared with the effects of AUCN. Furthermore, AICN shortened hospital stay and increased survival rates. Notably, AICN improved health-related quality of life as measured using the EORTC QLQ-C30 questionnaire. CONCLUSION: AICN provided more benefits and better postoperative outcomes than AUCN, suggesting its utility for minimizing complications in patients with breast cancer after surgery.

Diagnostic value of radionuclide in bone metastasis after breast cancer surgery: A protocol of systematic review.

BACKGROUND: The objective of this study is to evaluate the accuracy of radionuclide in diagnosis of bone metastasis (BM) after breast cancer surgery (BCS). METHODS: The electronic databases (Cochrane Library, MEDLINE, EMBASE, Web of Science, CBM, and CNKI) will be systematically and comprehensively searched until June 1, 2020 for eligible studies that reported the diagnosis of radionuclide in BM after BCS. In addition, we will also identify grey literatures, such as conference abstracts, and reference lists of included studies. All process of study identification, data extraction, and study methodological quality evaluation will be performed by 2 independent authors. All divergences will be settled by a third author through discussion. All data analysis will be carried out by RevMan 5.3 software (London, UK). RESULTS: This study will scrutinize the most recent evidence of radionuclide in detection of BM after BCS. CONCLUSION: This study may provide evidence of accuracy of radionuclide in diagnosis of BM following BCS. STUDY REGISTRATION NUMBER: PROSPERO CRD42020187646.

Circular RNAs add diversity to androgen receptor isoform repertoire in castration-resistant prostate cancer.

Deregulated expression of circular RNAs (circRNAs) is associated with various human diseases, including many types of cancer. Despite their growing links to cancer, there has been limited characterization of circRNAs in metastatic castration-resistant prostate cancer, the major cause of prostate cancer mortality. Here, through the analysis of an exome-capture RNA-seq dataset from 47 metastatic castration-resistant prostate cancer samples and ribodepletion and RNase R RNA-sequencing of patient-derived xenografts (PDXs) and cell models, we identified 13 circRNAs generated from the key prostate cancer driver gene-androgen receptor (AR). We validated and characterized the top four most abundant, clinically relevant AR circRNAs. Expression of these AR circRNAs was upregulated during castration-resistant progression of PDXs. The upregulation was not due to global increase of circRNA formation in these tumors. Instead, the levels of AR circRNAs correlated strongly with that of the linear AR transcripts (both AR and AR variants) in clinical samples and PDXs, indicating a transcriptional mechanism of regulation. In cultured cells, androgen suppressed the expression of these AR circRNAs and the linear AR transcripts, and the suppression was attenuated by an antiandrogen. Using nuclear/cytoplasmic fractionation and RNA in-situ hybridization assays, we demonstrated predominant cytoplasmic localization of these AR circRNAs, indicating likely cytoplasmic functions. Overall, this is the first comprehensive characterization of circRNAs arising from the AR gene. With greater resistance to exoribonuclease compared to the linear AR transcripts and detectability of AR circRNAs in patient plasma, these AR circRNAs may serve as surrogate circulating markers for AR/AR-variant expression and castration-resistant prostate cancer progression.

Macrolides Inhibit Capsule Formation of Highly Virulent Cryptococcus gattii and Promote Innate Immune Susceptibility.

Cryptococcus gattii is a fungal pathogen, endemic in tropical and subtropical regions, the west coast of Canada, and the United States, that causes a potentially fatal infection in otherwise healthy individuals. Because the cryptococcal polysaccharide capsule is a leading virulence factor due to its resistance against innate immunity, the inhibition of capsule formation may be a promising new therapeutic strategy for C. gattii Macrolides have numerous nonantibiotic effects, including immunomodulation of mammalian cells and suppression of bacterial (but not fungal) pathogenicity. Thus, we hypothesized that a macrolide would inhibit cryptococcal capsule formation and improve the host immune response. Coincubation with clarithromycin (CAM) and azithromycin significantly reduced the capsule thickness and the amount of capsular polysaccharide of both C. gattii and C. neoformans CAM-treated C. gattii cells were significantly more susceptible to H2O2 oxidative stress and opsonophagocytic killing by murine neutrophils. In addition, more C. gattii cells were phagocytosed by murine macrophages, resulting in increased production of tumor necrosis factor alpha (TNF-α) by CAM exposure. After CAM exposure, dephosphorylation of Hog1, one of the mitogen-activated protein kinase (MAPK) signaling pathways of Cryptococcus, was observed in Western blot analysis. In addition, CAM exposure significantly reduced the mRNA expression of LAC1 and LAC2 (such mRNA expression is associated with cell wall integrity and melanin production). These results suggest that CAM may aid in inhibiting capsular formation via the MAPK signaling pathway and by suppressing virulent genes; thus, it may be a useful adjunctive agent for treatment of refractory C. gattii infection.

IL-21 Enhances the Development of Colitis-Associated Colon Cancer: Possible Involvement of Activation-Induced Cytidine Deaminase Expression.

Inflammatory bowel diseases are known to be the origin of colitis-associated colon cancer (CAC). We previously reported that dextran sulfate sodium (DSS)-induced colitis is exacerbated in mouse-IL-21-isoform transgenic (Tg) mice. In this study, we assessed the CAC development induced by azoxymethane (AOM) and DSS in our Tg mice. AOM-DSS-induced tumor development was dramatically increased in the Tg mice compared with wild-type mice. IL-21 is known to enhance activation-induced cytidine deaminase (AID) expression in B cells and induce Ab class switching. In contrast, the AID expression in cells other than B cells initiates tumor development in many tissues. Therefore, we investigated whether IL-21 induces the AID expression in the large intestinal epithelial cells (IECs) during CAC development. AID gene and protein expression was increased in the IECs of AOM-DSS- or DSS-treated Tg mice compared with those of wild-type mice. Furthermore, we confirmed IL-21 induced AID gene expression in the purified IECs ex vivo. The present study also showed IL-21R gene expression in unstimulated wild-type mouse IECs, and this gene expression was augmented by TNF-α stimulation. The IL-21R expression and IL-21-induced AID gene activation were further confirmed in the Colon-38 cell line. Taken together, IL-21 may be involved in increasing the risk of CAC by enhancing the AID expression in IECs.

A positive role of c-Myc in regulating androgen receptor and its splice variants in prostate cancer.

Increased expression of the full-length androgen receptor (AR-FL) and AR splice variants (AR-Vs) drives the progression of castration-resistant prostate cancer (CRPC). The levels of AR-FL and AR-V transcripts are often tightly correlated in individual CRPC samples, yet our understanding of how their expression is co-regulated is limited. Here, we report a role of c-Myc in accounting for coordinated AR-FL and AR-V expression. Analysis of gene-expression data from 159 metastatic CRPC samples and 2142 primary prostate tumors showed that the level of c-Myc is positively correlated with that of individual AR isoforms. A striking positive correlation also exists between the activity of the c-Myc pathway and the level of individual AR isoforms, between the level of c-Myc and the activity of the AR pathway, and between the activities of the two pathways. Moreover, the c-Myc signature is highly enriched in tumors expressing high levels of AR, as is the AR signature in c-Myc-high-expressing tumors. Using shRNA knockdown, we confirmed c-Myc regulation of expression and activity of AR-FL and AR-Vs in cell models and a patient-derived xenograft model. Mechanistically, c-Myc promotes the transcription of the AR gene and enhances the stability of the AR-FL and AR-V proteins without altering AR RNA splicing. Importantly, inhibiting c-Myc sensitizes enzalutamide-resistant cells to growth inhibition by enzalutamide. Overall, this study highlights a critical role of c-Myc in regulating the coordinated expression of AR-FL and AR-Vs that is commonly observed in CRPC and suggests the utility of targeting c-Myc as an adjuvant to AR-directed therapy.

Caloric restriction counteracts chemotherapy-induced inflammation and increases response to therapy in a triple negative breast cancer model.

Triple negative breast cancer (TNBC) is a heterogeneous disease that has no available targeted therapies. Previously, we have shown that caloric restriction (CR) can augment the effects of radiation therapy in a TNBC mouse model. To build upon this, we now present data regarding the combination of chemotherapy and CR in the same 4T1 model. Chemotherapy can induce inflammation that breeds resistance to therapy. We propose CR as a mechanism to decrease chemotherapy-induced inflammation and increase efficacy of therapy. 12-week old Balb/c mice were orthotopically injected with a syngeneic triple negative breast cancer cell line (4T1) and were treated in one of six cohorts: ad lib fed (AL), 30% reduction in calorie intake (CR), cisplatin or docetaxol alone or a combination CR+cisplatin/docetaxol. Mice in the cohorts receiving chemotherapy+CR had longer overall survival (12 ± 2 days) as compared to the AL group. These mice also demonstrated less lung metastases at the final time point of in vivo imaging. In addition, downregulation of the IGF-1R and IRS signaling pathways were noted most significantly in those mice receiving combination therapy. Lastly, serum from these mice demonstrated an increase in inflammatory cytokines TNF-α and IL-1ß in response to chemotherapy alone. This increase was dampened by the addition of CR. Taken together, these data suggest that while chemotherapy is effective in TNBC, it can cause inflammation, which can be a driver of resistance to therapy. This chemotherapy-induced inflammation can be reversed with the use of CR as a nontoxic adjunct to treatment.

A retrospective study of alendronate for the treatment of ankylosing spondylitis.

This retrospective study assessed the effect of alendronate for treating patients with ankylosing spondylitis (AS).Eighty-six patients with AS were included in this retrospective study, and were divided into 2 groups. Forty-six patients in the intervention group received alendronate plus vitamin D (400 mg/day) and calcium (500 mg/day), while 40 patients in the control group received vitamin D and calcium only, the same dose as the intervention group. The primary outcome included bone densitometry. The secondary outcomes consisted of quality of life, measured by Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire, disease activity, measured by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and functional status, measured by Bath Ankylosing Spondylitis Functional Index (BASFI), as well as the adverse events (AEs).At the end of 6-month treatment, patients in the intervention group were not superior to the patients in the control group in bone densitometry (hip, P = .47; lumbar, P = .53), quality of life (P = .32), disease activity (P = .39), and functional status (P = .41). Moreover, no significant differences in AEs were found between 2 groups.The results of the present study showed that alendronate can neither be used to treat bone loss, nor to enhance the quality of life, disease activity, and functional status.

Protein Tyrosine Phosphatase SHP-2 Is Involved in the Interleukin-21-Induced Activation of Extracellular Signal-Regulated Kinase 1/2.

The cytokine interleukin-21 (IL-21) is mainly produced from activated CD4+ T cells and natural killer T (NKT) cells. IL-21 enhances the proliferation and differentiation of T cells and B cells and also increases cytotoxicity of CD8+ T cells and NK cells through the IL-21 receptor and its downstream signaling molecules such as signal transducers and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2). SH2 domain-containing tyrosine phosphatase (SHP-2) is ubiquitously expressed, including hematopoietic cells. SHP-2 has been implicated in the regulation of IL-6 and IL-3 signaling, but its function in IL-21 signaling has not been investigated. Therefore, we studied the role of SHP-2 in IL-21 signaling by SHP-2 overexpression and knockdown experiments. For the SHP-2 overexpression, we used 293T human embryonic kidney cells, in which the IL-21 receptor system were easily reconstituted and high amounts of exogenous SHP-2 were expressed by vector transfection. In 293T cells, overexpressed SHP-2 caused the increase in the degree of the IL-21-induced ERK1/2 activation. Subsequently, SHP-2 knockdown experiments were performed in the mouse pro-B cell line, BAF21RWT-1, which constitutively expresses human IL-21 receptor and proliferates in an IL-21-dependent manner. SHP-2 knockdown reduced the degree of the IL-21-induced ERK1/2 activation and suppressed cell proliferation. These results suggest that SHP-2 may augment the ERK1/2 activity and cell proliferation activity in IL-21 signaling. We propose that SHP-2 is involved in the IL-21-mediated ERK1/2 activation and cell proliferation.

Thoracic paravertebral regional anesthesia for pain relief in patients with breast cancer surgery.

BACKGROUND: The present study aimed to assess the efficacy and safety of thoracic paravertebral regional anesthesia (TPVBRA) in patients with breast cancer surgery. METHODS: In total, 72 patients undergoing breast cancer surgery were randomly divided into an intervention group and a control group; each group contained 36 subjects. Both groups received TPVBRA with 20 mL 0.25% bupivacaine. In addition, subjects in the intervention group also received an additional 1 µg/kg dexmedetomidine. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), pain intensity (measured by visual analogue scale, VAS), and analgesic consumption were assessed; adverse events were also recorded. RESULTS: Significant differences were observed in HR (P < .05), SBP (P < .05), and DBP (P < .05) at the 30-minute point during surgery between the 2 groups. In addition, the time of the first administration of analgesia (P = .043) and the mean consumption of analgesic agents (P = .035) in the intervention group were much better than those in the control group. However, no significant differences in HR or VAS were found at any time point after surgery (P > .05). Furthermore, similar adverse events were detected in both groups (P > .05). CONCLUSION: The results of this study showed that TPVBRA combined with bupivacaine and dexmedetomidine can enhance the duration and quality of analgesia without serious adverse events.

A randomized controlled trial of botulinum toxin A for treating neuropathic pain in patients with spinal cord injury.

BACKGROUND: To assess the effect of botulinum toxin A (BTA) for treating neuropathic pain in patients with spinal cord injury (SCI). METHODS: A total of 44 patients with SCI with neuropathic pain were randomly divided into the intervention group and the placebo group, each group 21 patients. The subjects in the intervention group received BTA (200 U subcutaneous injection, once daily) at the painful area, whereas those in the placebo group were administered a saline placebo. This study was conducted from December 2014 to November 2016. The primary outcome was measured using the visual analog scale (VAS). The secondary outcomes were measured using the short-form McGill Pain Questionnaire (SF-MPQ), and World Health Organization quality of life (WHOQOL-BREF) questionnaire. All outcome measurements were performed before and after 4 and 8 weeks of intervention. RESULTS: Forty-one participants completed the study. The intervention with BTA showed greater efficacy than placebo in decreasing the VAS score after week 4 and week 8 of treatment. Significant differences in the SF-MPQ and WHOQOL-BREF were also found between the 2 groups. CONCLUSION: The results of this study demonstrated that BTA might decrease intractable neuropathic pain for patients with SCI.

Efficacy and safety of remifentanil for analgesia in cesarean delivery.

BACKGROUND: This study aimed to assess the efficacy and safety of remifentanil as a general anesthetic during cesarean delivery. MATERIAL AND METHODS: Fifty women with singleton pregnancies undergoing cesarean delivery were randomly divided into intervention and control groups, each group containing 25 subjects. Participants in the intervention group received remifentanil (infused at 2 µg/kg/h), whereas subjects in the control group were given dexmedetomidine (infused at 0.4 µg/kg/h). Outcome measurements included mean arterial blood pressure (MAP), heart rate (HR), bispectral index (BIS), Apgar scores at 1 and 5 minutes, and the pH, PCO2, PO2, and base excess (BE) of umbilical venous and arterial blood. RESULTS: Forty-four participants completed the study. Patients in the intervention group did not experience greater effect and safety than those in the control group (P > .05), although MAP and BIS values decreased significantly immediately before laryngoscopy (P < .05). In addition, BIS values were reduced significantly at the time of skin incision, at uterine incision, and immediately after fetal delivery when compared with baseline values in both groups (P < .01). CONCLUSION: This study concluded that remifentanil and dexmedetomidine exhibited similar efficacy and safety during general anesthesia for cesarean delivery.

Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer.

PURPOSE: Metastatic breast cancer is devastating and triple negative breast cancers (TNBC) have a higher propensity for metastasis. Improved local control upfront in this aggressive cancer could potentially decrease its propensity toward metastasis. We sought to determine if using caloric restriction (CR) as a systemic therapy, combined with radiation therapy (IR) to the primary tumor, may impact metastatic disease. METHODS: An orthotopic mouse model using a highly metastatic, luciferase-tagged TNBC cell line (4T1), was used to generate palpable tumors. Mice were then treated with CR, IR, and a combination of the two. In vivo imaging was performed for metastatic evaluation. Molecular evaluation of the tumors was performed, generating a mechanistic hypothesis for CR, which was then tested with pertinent pathway inhibition in the model. RESULTS: CR significantly increased the time to developing metastases, decreased the overall number and volume of lung metastases, and increased survival. CR decreased proliferation, increased apoptosis and globally downregulated the IGF-1R signaling pathway. Adding an IGF-1R/INSR inhibitor to local IR in vivo accomplished a decrease in metastases similar to CR plus IR, demonstrating the importance of the IGF-1R signaling pathway, and underscoring it as a possible mechanism for CR. CONCLUSIONS: CR decreased metastatic burden and therefore may complement cytotoxic therapies being used in the clinical setting for metastatic disease. Downregulation of the IGF-1R pathway, is in part responsible for this response and modulating IGF-1R directly resulted in similar improved progression-free survival. The novel use of CR has the potential to enhance clinical outcomes for patients with metastatic breast cancer.

microRNA alterations driving acute and late stages of radiation-induced fibrosis in a murine skin model.

PURPOSE: Although ionizing radiation is critical in treating cancer, radiation-induced fibrosis (RIF) can have a devastating impact on patients' quality of life. The molecular changes leading to radiation-induced fibrosis must be elucidated so that novel treatments can be designed. METHODS AND MATERIALS: To determine whether microRNAs (miRs) could be responsible for RIF, the fibrotic process was induced in the right hind legs of 9-week old CH3 mice by a single-fraction dose of irradiation to 35 Gy, and the left leg served as an unirradiated control. Fibrosis was quantified by measurements of leg length compared with control leg length. By 120 days after irradiation, the irradiated legs were 20% (P=.013) shorter on average than were the control legs. RESULTS: Tissue analysis was done on muscle, skin, and subcutaneous tissue from irradiated and control legs. Fibrosis was noted on both gross and histologic examination by use of a pentachrome stain. Microarrays were performed at various times after irradiation, including 7 days, 14 days, 50 days, 90 days, and 120 days after irradiation. miR-15a, miR-21, miR-30a, and miR-34a were the miRs with the most significant alteration by array with miR-34a, proving most significant on confirmation by reverse transcriptase polymerase chain reaction, c-Met, a known effector of fibrosis and downstream molecule of miR-34a, was evaluated by use of 2 cell lines: HCT116 and 1522. The cell lines were exposed to various stressors to induce miR changes, specifically ionizing radiation. Additionally, in vitro transfections with pre-miRs and anti-miRs confirmed the relationship of miR-34a and c-Met. CONCLUSIONS: Our data demonstrate an inverse relationship with miR-34a and c-Met; the upregulation of miR-34a in RIF causes inhibition of c-Met production. miRs may play a role in RIF; in particular, miR-34a should be investigated as a potential target to prevent or treat this devastating side effect of irradiation.

MicroRNA expression altered by diet: can food be medicinal?

As the link between metabolism and major disease processes becomes more well-defined, the identification of key molecular targets is leading to new therapeutic strategies. As a result, small non-coding RNA molecules that regulate gene expression via epigenetic alterations, microRNAs have been identified as regulators of these metabolic processes. In the last decade, dietary interventions have been used to change metabolism and to potentially alter disease progression and clinical outcomes. These interventions have been linked, at a molecular level, to microRNAs. This review will summarize the role of various dietary strategies on the expression of several microRNA families.

The metastatic potential of triple-negative breast cancer is decreased via caloric restriction-mediated reduction of the miR-17~92 cluster.

Caloric restriction (CR) has been shown to cause tumor regression in models of triple-negative breast cancer (TNBC), and the regression is augmented when coupled with ionizing radiation (IR). In this study, we sought to determine if the molecular interaction between CR and IR could be mediated by microRNA (miR). miR arrays revealed 3 miRs in the miR-17~92 cluster as most significantly down regulated when CR is combined with IR. In vivo, CR and IR down regulated miR-17/20 in 2 TNBC models. To elucidate the mechanism by which this cluster regulates the response to CR, cDNA arrays were performed and the top 5 statistically significant gene ontology terms with high fold changes were all associated with extracellular matrix (ECM) and metastases. In silico analysis revealed 4 potential targets of the miR-17~92 cluster related to ECM: collagen 4 alpha 3, laminin alpha 3, and metallopeptidase inhibitors 2 and 3, which were confirmed by luciferase assays. The overexpression or silencing of miR-17/20a demonstrated that those miRs directly affected the ECM proteins. Furthermore, we found that CR-mediated inhibition of miR-17/20a can regulate the expression of ECM proteins. Functionally, we demonstrate that CR decreases the metastatic potential of cells which further demonstrates the importance of the ECM. In conclusion, CR can be used as a potential treatment for cancer because it may alter many molecular targets concurrently and decrease metastatic potential for TNBC.

Caloric restriction augments radiation efficacy in breast cancer.

Dietary modification such as caloric restriction (CR) has been shown to decrease tumor initiation and progression. We sought to determine if nutrient restriction could be used as a novel therapeutic intervention to enhance cytotoxic therapies such as radiation (IR) and alter the molecular profile of triple-negative breast cancer (TNBC), which displays a poor prognosis. In two murine models of TNBC, significant tumor regression is noted with IR or diet modification, and a greater regression is observed combining diet modification with IR. Two methods of diet modification were compared, and it was found that a daily 30% reduction in total calories provided more significant tumor regression than alternate day feeding. At the molecular level, tumors treated with CR and IR showed less proliferation and more apoptosis. cDNA array analysis demonstrated the IGF-1R pathway plays a key role in achieving this physiologic response, and multiple members of the IGF-1R pathway including IGF-1R, IRS, PIK3ca and mTOR were found to be downregulated. The innovative use of CR as a novel therapeutic option has the potential to change the biology of tumors and enhance the opportunity for clinical benefit in the treatment of patients with TNBC.

Role of interleukin-21 isoform in dextran sulfate sodium (DSS)-induced colitis.

Interleukin-21 (IL-21) is overproduced in human intestines affected by inflammatory bowel disease (IBD) and in the gut of mice with DSS-induced colitis. IL-21-deficient mice are largely protected against DSS-induced colitis, indicating that IL-21 plays a key role in the development of IBD. We previously identified a novel IL-21 isoform named IL-21iso. In this study, we found that in addition to the conventional IL-21, IL-21iso mRNA was also expressed in the colon with DSS-induced colitis. To investigate whether IL-21iso plays a role in DSS-induced colitis, we established transgenic mice (mIL-21iso-Tg mice) that expressed mouse IL-21iso under the control of the lck proximal promoter. Although mIL-21iso-Tg mice did not have any gross physical abnormalities, their peripheral lymphocytes counts were higher than those in wild-type littermates. Notably, their CD8(+) T cell and CD4(+) effector memory T-cell populations were elevated. DSS-induced colitis was far more severe in the mIL-21iso-Tg mice than in wild-type mice, and was accompanied by a marked loss of body weight and by colon inflammation with increased cellular infiltration. In DSS-treated mice, colon tissues from mIL-21iso-Tg mice had significantly higher gene activation levels for cytokines such as IL-17A, TNF-α, IL-6, IL-10, and IL-4, and for transcription factors such as T-bet, GATA-3, RORγt, and Foxp3, than were found in wild-type mice. These results indicate that besides IL-21, IL-21iso may be another regulator of gut inflammation.