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Jane Gerber, M.S.W., a long time trusted friend, colleague and student of Virginia Satir, is featured in this lively interview which was conducted in late 2006. Gerber presents an in-depth view of Satir from her early days in Chicago when Satir first began her work with families and was rapidly establishing her reputation as a trainer for her newly developed systemic approach to therapeutic work. Her new and powerful methods as well as her style of teaching drew the interest of leaders in the therapeutic community. Gerber also presents an intimate and sensitive portrait of Satir's personal life as well as her work. [ABSTRACT FROM AUTHOR]

In this interview, the reader is offered a glimpse of Virginia Satir through the eyes of one of her trusted colleagues, Dr. Bunny Duhl. While the author conducted and videotaped 18 interviews of elder therapists in Avanta, now known as the "Virginia Satir Global Network" (VSGN), this interview is the first that has showcased in its entirety. The interview gives the reader a taste of Virginia Satir's influence on the many talented people who trained with her. Satir reveals herself to Bunny Duhl as the brilliant therapist, educator, change agent, creative spirit for which she was known around the world. But the interview also sensitively reveals the disparagement and personal and professional attacks Satir weathered over the years from her male colleagues in the early family therapy movement. She had radical ideas, radical methods, and she always questioned the status quo. Her colleagues wanted to compete in academia and in the research world. Family Therapy was still trying to qualify as a legitimate approach. The interview also touches the edges of evident sexism that was apparent but unacknowledged. Revealed also are bits and pieces of Satir's shadow side, her personal challenges and her very human struggle to stay congruent. [ABSTRACT FROM AUTHOR]

It has been previously shown that the cytokine interleukin 33 is required for two processes, i.e., autophagic digestion of granulosa cells and recruitment of macrophages into atretic follicles, for full disposal of atretic follicles. Now, this study shows that activation of interleukin 33-suppression of tumorigenicity 2-Nuclear Factor ĸB (NFκB) axis in granulosa in early atretic follicles may regulate those two events. Injection of human chorionic gonadotropin has been shown to induce a transient peak of interleukin 33 expression with synchronized atresia. In this model, interleukin 33-independent expression of suppression of tumorigenicity 2 in granulosa cells was detected in early atretic follicles before macrophage invasion. The activation of NFκB pathway in ovaries was further demonstrated in vivo in Tg mice with luciferase-reporter for NFκB activation; the activation was microscopically localized to granulosa cells in early atretic follicles. Importantly, antibody blockage of interleukin 33 or interleukin 33 Knock-out (KO) (Il33-/-) not only inhibited NFκB activity in ovaries, but it also altered expression of two key genes, i.e., reduction in proinflammatory interleukin6 (IL6) expression, and a surge of potential autophagy-inhibitory mammalian target of rapamycin (mTOR) expression in atretic follicles. By contrast, apoptosis and other genes, such as interleukin1β (IL1β) were not affected. In conclusion, in parallel to apoptosis, atresia signals also trigger activation of the interleukin 33-suppression of tumorigenicity 2-NFκB pathway in granulosa, which leads to (1) down-regulated expression of mTOR that is a negative regulator of autophagy and (2) up-regulated expression of proinflammatory IL6., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The phosphatases of regenerating liver (PRL) are oncogenic when overexpressed. We previously found that PRL2 deletion increases PTEN, decreases Akt activity, and suppresses tumor development in a partial Pten-deficient mouse model. The current study aims to further establish the mechanism of PTEN regulation by PRL2 and expand the therapeutic potential for PTEN augmentation mediated by PRL2 inhibition in cancers initiated without PTEN alteration. The TP53 gene is the most mutated tumor suppressor in human cancers, and heterozygous or complete deletion of Tp53 in mice leads to the development of sarcomas and thymic lymphomas, respectively. There remains a lack of adequate therapies for the treatment of cancers driven by Tp53 deficiency or mutations. We show that Prl2 deletion leads to PTEN elevation and attenuation of Akt signaling in sarcomas and lymphomas developed in Tp53 deficiency mouse models. This results in increased survival and reduced tumor incidence because of impaired tumor cell proliferation. In addition, inhibition of PRL2 with a small-molecule inhibitor phenocopies the effect of genetic deletion of Prl2 and reduces Tp53 deficiency-induced tumor growth. Taken together, the results further establish PRL2 as a negative regulator of PTEN and highlight the potential of PRL2 inhibition for PTEN augmentation therapy in cancers with wild-type PTEN expression., Significance: Prl2 deletion attenuates Tp53 deficiency-induced tumor growth by increasing PTEN and reducing Akt activity. Targeting Tp53-null lymphoma with PRL inhibitors lead to reduced tumor burden, providing a therapeutic approach via PTEN augmentation., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Overexpression of phosphatases of regenerating liver 2 (PRL2), detected in numerous diverse cancers, is often associated with increased severity and poor patient prognosis. PRL2-catalyzed tyrosine dephosphorylation of the tumor suppressor PTEN results in increased PTEN degradation and has been identified as a mechanism underlying PRL2 oncogenic activity. Overexpression of PRL2, coincident with reduced PTEN protein, is frequently observed in patients with acute myeloid leukemia (AML). In the current study, a PTEN-knockdown AML animal model was generated to assess the effect of conditional PRL2 inhibition on the level of PTEN protein and the development and progression of AML. Inhibition of PRL2 resulted in a significant increase in median animal survival, from 40 weeks to greater than 60 weeks. The prolonged survival reflected delayed expansion of aberrantly differentiated hematopoietic stem cells into leukemia blasts, resulting in extended time required for clinically relevant leukemia blast accumulation in the BM niche. Leukemia blast suppression following PRL2 inhibition was correlated with an increase in PTEN and downregulation of AKT/mTOR-regulated pathways. These observations directly established, in a disease model, the viability of PRL2 inhibition as a therapeutic strategy for improving clinical outcomes in AML and potentially other PTEN-deficient cancers by slowing cancer progression.

Defective aquaporin4 (AQP4)-mediated glymphatic drainage has been linked to tauopathy and amyloid plaque in Alzheimer's disease. We now show that brain interleukin33 (IL33) is required for regulation of AQP4 expression in astrocytes, especially those at neuron-facing membrane domain (n-AQP4). First, IL33-deficient (Il33 -/- ) mice showed a loss of n-AQP4 after middle age, which coincided with a rapid accumulation of abnormal tau in neurons and a reduction in drainage of abnormal tau to peripheral tissues. Second, injection of recombinant IL33 induced robust expression of AQP4 at perivascular endfoot (p-AQP4) of astrocytes, but not n-AQP4, in Il33 -/- brains. Although the increased p-AQP4 greatly accelerated drainage of intracerebroventricularly injected peptides, it did not substantially accelerate drainage of abnormal tau. These results suggest that p-AQP4 drives overall convective flow toward perivenous space, i.e., glymphatics, whereas n-AQP4 may generate an aqueous flow away from neurons to remove neuronal wastes, e.g., abnormal tau. We have previously shown the role of brain IL33 in DNA repair and autophagy in neurons with oxidative stress. Now, we show that IL33 deficiency also impairs glymphatic drainage. Defects in those mechanisms together may lead to chronic neurodegeneration and tauopathy at old age in IL33-deficient mice., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)

Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) levels are frequently found reduced in human cancers, but how PTEN is down-regulated is not fully understood. In addition, although a compelling connection exists between PRL (phosphatase of regenerating liver) 2 and cancer, how this phosphatase induces oncogenesis has been an enigma. Here, we discovered that PRL2 ablation inhibits PTEN heterozygosity-induced tumorigenesis. PRL2 deficiency elevates PTEN and attenuates AKT signaling, leading to decreased proliferation and increased apoptosis in tumors. We also found that high PRL2 expression is correlated with low PTEN level with reduced overall patient survival. Mechanistically, we identified PTEN as a putative PRL2 substrate and demonstrated that PRL2 down-regulates PTEN by dephosphorylating PTEN at Y336, thereby augmenting NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Given the strong cancer susceptibility to subtle reductions in PTEN, the ability of PRL2 to down-regulate PTEN provides a biochemical basis for its oncogenic propensity. The results also suggest that pharmacological targeting of PRL2 could provide a novel therapeutic strategy to restore PTEN, thereby obliterating PTEN deficiency-induced malignancies., Competing Interests: The authors declare no competing interest.

Inter-molecular epitope spreading during autoimmune pathogenesis leads to generation of new pathogenic epitopes on other autoantigens beyond the original one. It raises an important question as whether autoimmunity extends beyond the target tissues if new epitopes are on the molecules shared with other tissues. This study is aimed addressing this question in a rat anti-glomerular basement membrane (GBM) glomerulonephritis model induced by a T cell epitope of glomerulus-specific collagen4α3. We have demonstrated inter-molecular B cell epitope spreading. Four novel epitopes were first identified by screening a phage display random peptide library against autoantibodies isolated from the GBM of immunized rats. All four epitopes were derived from GBM proteins with three from laminins and one from collagen4α4. Three out of four synthetic peptides were nephritogenic. Importantly, two peptides from lamininα1 and lamininβ1, respectively, induced severe inflammation in glomeruli but not in the interstitial tissues, despite the presence of more abundant laminins in the tubular basement membranes. Our study suggests that surrounding tissues may display a lower or altered susceptibility to autoimmune inflammation. Thus, preventing extension of autoimmune inflammation beyond the original target tissue., Competing Interests: The authors have declared that no competing interests exist.

Polo-like kinase 1 (Plk1), a crucial regulator of cell-cycle progression, is overexpressed in multiple types of cancers and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that antineoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the β-catenin pathway and increased expression of c-MYC, eventually resulting in resistance to Plk1 inhibition. JQ1, a selective small-molecule inhibitor targeting the amino-terminal bromodomains of BRD4, has been shown to dramatically inhibit c-MYC expression and AR signaling, exhibiting antiproliferative effects in a range of cancers. Because c-MYC and AR signaling are essential for prostate cancer initiation and progression, we aim to test whether targeting Plk1 and BRD4 at the same time is an effective approach to treat prostate cancer. Herein, we show that a combination of Plk1 inhibitor GSK461364A and BRD4 inhibitor JQ1 had a strong synergistic effect on castration-resistant prostate cancer (CRPC) cell lines, as well as in CRPC xenograft tumors. Mechanistically, the synergistic effect is likely due to two reasons: (i) Plk1 inhibition results in the accumulation of β-catenin in the nucleus, thus elevation of c-MYC expression, whereas JQ1 treatment directly suppresses c-MYC transcription; (ii) Plk1 and BRD4 dual inhibition acts synergistically in inhibition of AR signaling. Mol Cancer Ther; 17(7); 1554-65. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Alzheimer's Disease or other dementias are characterized by the accumulation of abnormal tau and amyloid β peptides in brains. Therefore, abnormal tau and amyloid peptides in peripheral tissues or blood have been explored as diagnostic biomarkers. On the other hand, recent studies have revealed glymphatics a special drainage system for brain's wastes. We aimed to investigate whether effectiveness of glymphatic system affects the quantity of abnormal tau in the peripheral tissues. We have previously shown that aged IL33 KO ( Il33 -/- ) mice develop Alzheimer's like disease. Despite a large quantity of abnormal tau in brains, Il33 -/- mice showed a much lower amount of abnormal tau drained to the peripheral tissues kidneys than in wild type mice. Our further study showed that it was caused by defective glymphatic drainage since Il33 KO impaired glymphatics. Thus, it is necessary to identify biomarkers, which can evaluate efficiency of glymphatic drainage. Simultaneous measurement of these biomarkers and abnormal tau in peripheral tissues or blood may be critical for accurate diagnosis of Alzheimer's disease., Competing Interests: Conflict of Interest All authors declare no conflict of interests.

MDC1 is a central player in checkpoint activation and subsequent DNA repair following DNA damage. Although MDC1 has been studied extensively, many of its known functions, to date, pertain to the DNA damage response (DDR) pathway. Herein we report a novel function of phosphorylated MDC1 that is independent of ATM and DNA damage and is required for proper mitotic progression and maintenance of genomic stability. We demonstrate that MDC1 is an in vivo target of Plk1 and that phosphorylated MDC1 is dynamically localized to nuclear envelopes, centrosomes, kinetochores, and midbodies. Knockdown of MDC1 or abrogation of Plk1 phosphorylation of MDC1 causes a delay of the prometaphase-metaphase transition. It is significant that mice with reduced levels of MDC1 showed an elevated level of spontaneous tumors in aged animals. Our results demonstrate that MDC1 also plays a fundamentally significant role in maintenance of genomic stability through a DDR-independent pathway., (Copyright © 2017 American Society for Microbiology.)

Olaparib is an FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data have also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors. Herein, by combination with Plk1 inhibitor BI2536, we show a robust sensitization of olaparib in 22RV1, a BRCA1-deficient CRPC cell line, as well as in CRPC xenograft tumors. Mechanistically, monotherapy with olaparib results in an override of the G 1 -S checkpoint, leading to high expression of Plk1, which attenuates olaparib's overall efficacy. In BRCA1 wild-type C4-2 cells, Plk1 inhibition also significantly increases the efficacy of olaparib in the presence of p53 inhibitor. Collectively, our findings not only implicate the critical role of Plk1 in PARPi resistance in BRCA-mutant CRPC cells, but also shed new light on the treatment of non-BRCA-mutant patient subgroups who might also respond favorably to PARPi. Mol Cancer Ther; 16(3); 469-79. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Discovery of immune tolerance mechanisms, which inhibit pre-existing autoimmune inflammation, may provide us with new strategies for treating autoimmune diseases. We have identified a CD8αα + MHC class II + cell with professional APC capacity during our investigation on spontaneous recovery from autoimmune glomerulonephritis in a rat model. This cell actively invades inflamed target tissue and further terminates an ongoing autoimmune inflammation by selective killing of effector autoreactive T cells. In this study, we show that this cell used a cytotoxic machinery of Ly49s + NK cells in killing of target T cells. Thus, this CD8αα + MHC class II + cell was a dually functional Ag-presenting NK-like (AP-NK) cell. Following its coupling with target T cells through Ag presentation, killing stimulatory receptor Ly49s6 and coreceptor CD8αα on this cell used rat nonclassic MHC class I C/E16 on the target T cells as a ligand to initiate killing. Thus, activated effector T cells with elevated expression of rat nonclassic MHC class I C/E16 were highly susceptible to the killing by the CD8αα + AP-NK cell. Granule cytolytic perforin/granzyme C from this cell subsequently mediated cytotoxicity. Thus, inhibition of granzyme C effectively attenuated the killing. As it can recognize and eliminate effector autoreactive T cells in the inflamed target tissue, the CD8αα + AP-NK cell not only represents a new type of immune cell involved in immune tolerance, but it also is a potential candidate for developing a cell-based therapy for pre-existing autoimmune diseases., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Extensive reprogramming of cellular energy metabolism is a hallmark of cancer. Despite its importance, the molecular mechanism controlling this tumour metabolic shift remains not fully understood. Here we show that 14-3-3σ regulates cancer metabolic reprogramming and protects cells from tumorigenic transformation. 14-3-3σ opposes tumour-promoting metabolic programmes by enhancing c-Myc poly-ubiquitination and subsequent degradation. 14-3-3σ demonstrates the suppressive impact on cancer glycolysis, glutaminolysis, mitochondrial biogenesis and other major metabolic processes of tumours. Importantly, 14-3-3σ expression levels predict overall and recurrence-free survival rates, tumour glucose uptake and metabolic gene expression in breast cancer patients. Thus, these results highlight that 14-3-3σ is an important regulator of tumour metabolism, and loss of 14-3-3σ expression is critical for cancer metabolic reprogramming. We anticipate that pharmacologically elevating the function of 14-3-3σ in tumours could be a promising direction for targeted anticancer metabolism therapy development in future.

Physiological processes such as ovarian follicle atresia generate large amounts of unnecessary cells or tissue detritus, which needs to be disposed of rapidly. IL-33 is a member of the IL-1 cytokine gene family. Constitutive expression of IL-33 in a wide range of tissues has hinted at its role beyond immune defense. We have previously reported a close correlation between IL-33 expression patterns and ovarian atresia. In this study, we demonstrated that IL-33 is required for disposal of degenerative tissue during ovarian atresia using Il33(-/-) mice. Deletion of the Il33 gene impaired normal disposal of atretic follicles, resulting in massive accumulations of tissue wastes abundant with aging-related catabolic wastes such as lipofuscin. Accumulation of tissue wastes in Il33(-/-) mice, in turn, accelerated ovarian aging and functional decline. Thus, their reproductive life span was shortened to two thirds of that for Il33(+/-) littermates. IL-33 orchestrated disposal mechanism through regulation of autophagy in degenerating tissues and macrophage migration into the tissues. Our study provides direct evidence supporting an expanded role of IL-33 in tissue integrity and aging through regulating disposal of unnecessary tissues or cells., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Background: Obesity increases the risk of cancer death among postmenopausal women with estrogen receptor-positive (ER+) breast cancer, but the direct evidence for the mechanisms is lacking. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating this epidemiologic phenomenon., Methods: We analyzed transcriptomic profiles of pretreatment biopsies from a prospective cohort of 137 ER+ breast cancer patients. We generated transgenic (MMTV-TGFα;A (y) /a) and orthotopic/syngeneic (A (y) /a) obese mouse models to investigate the effect of obesity on tumorigenesis and tumor progression and to determine biological mechanisms using whole-genome transcriptome microarrays and protein analyses. We used a coculture system to examine the impact of adipocytes/adipokines on breast cancer cell proliferation. All statistical tests were two-sided., Results: Functional transcriptomic analysis of patients revealed the association of obesity with 59 biological functional changes (P < .05) linked to cancer hallmarks. Gene enrichment analysis revealed enrichment of AKT-target genes (P = .04) and epithelial-mesenchymal transition genes (P = .03) in patients. Our obese mouse models demonstrated activation of the AKT/mTOR pathway in obesity-accelerated mammary tumor growth (3.7- to 7.0-fold; P < .001; n = 6-7 mice per group). Metformin or everolimus can suppress obesity-induced secretion of adipokines and breast tumor formation and growth (0.5-fold, P = .04; 0.3-fold, P < .001, respectively; n = 6-8 mice per group). The coculture model revealed that adipocyte-secreted adipokines (eg, TIMP-1) regulate adipocyte-induced breast cancer cell proliferation and invasion. Metformin suppress adipocyte-induced cell proliferation and adipocyte-secreted adipokines in vitro., Conclusions: Adipokine secretion and AKT/mTOR activation play important roles in obesity-accelerated breast cancer aggressiveness in addition to hyperinsulinemia, estrogen signaling, and inflammation. Metformin and everolimus have potential for therapeutic interventions of ER+ breast cancer patients with obesity., (© The Author 2014. Published by Oxford University Press.)

In an anti-glomerular basement membrane (GBM) glomerulonephritis (GN) model, GN-resistant Lewis rats naturally recover from early glomerular inflammation. Here we investigated recovery mechanisms for development of a potential immunotherapy for autoimmune GN. Our previous studies suggested that glomeruli-infiltrating leukocytes with a phenotype of CD8αα+CD11c+MHC-II+CD3- (GIL CD8αα+ cells) were responsible for recovery through induction of T-cell apoptosis. Now, we identified peripheral blood CD8αα+CD11c+MHC-II+CD3- cells (PBMC CD8αα+CD3- cells), which shared 9 markers with GIL CD8αα+ cells. Upon incubation, PBMC CD8αα+CD3- cells displayed a morphology resembling that of dendritic cells. Similar to GIL CD8αα+ cells, PBMC CD8αα+CD3- cells were capable of inducing T-cell apoptosis in vitro. Hence, PBMC CD8αα+CD3- cells were likely the precursor of GIL CD8αα+ cells. We next tested their potential in vivo function. PBMC CD8αα+CD3- cells were able to infiltrate inflamed but not normal glomeruli. Isolated PBMC CD8αα+CD3- cells of Lewis rats were transferred into GN-prone Wistar-Kyoto rats at early inflammatory stage (days 17-25). When examined at day 45, both histopathology and blood urea nitrogen/serum creatinine level showed significantly attenuated GN in 80% of cell recipient Wistar-Kyoto rats. Separate experiments verified infiltration of transferred Lewis PBMC CD8αα+CD3- into the glomeruli, accompanied with apoptotic CD4+ T cells in the glomeruli of the recipient Wistar-Kyoto rats. Thus, PBMC CD8αα+CD3- cells of Lewis rats were able to terminate ongoing autoimmune inflammation in the glomeruli.

Ovarian macrophages, which play critical roles in various ovarian events, are probably derived from multiple lineages. Thus, a systemic classification of their subsets is a necessary first step for determination of their functions. Utilizing antibodies to five phagocyte markers, i.e. IA/IE (major histocompatibility complex class II), F4/80, CD11b (Mac-1), CD11c, and CD68, this study investigated subsets of ovarian phagocytes in mice. Three-color immunofluorescence and flow cytometry, together with morphological observation on isolated ovarian cells, demonstrated complicated phenotypes of ovarian phagocytes. Four macrophage and one dendritic cell subset, in addition to many minor phagocyte subsets, were identified. A dendritic cell-like population with a unique phenotype of CD11c(high)IA/IE⁻F4/80⁻ was also frequently observed. A preliminary age-dependent study showed dramatic increases in IA/IE⁺ macrophages and IA/IE⁺ dendritic cells after puberty. Furthermore, immunofluorescences on ovarian sections showed that each subset displayed a distinct tissue distribution pattern. The pattern for each subset may hint to their role in an ovarian function. In addition, partial isolation of ovarian macrophage subset using CD11b antibodies was attempted. Establishment of this isolation method may have provided us a tool for more precise investigation of each subset's functions at the cellular and molecular levels.

Aurora B is a mitotic checkpoint kinase that plays a pivotal role in the cell cycle, ensuring correct chromosome segregation and normal progression through mitosis. Aurora B is overexpressed in many types of human cancers, which has made it an attractive target for cancer therapies. Tumor suppressor p53 is a genome guardian and important negative regulator of the cell cycle. Whether Aurora B and p53 are coordinately regulated during the cell cycle is not known. We report that Aurora B directly interacts with p53 at different subcellular localizations and during different phases of the cell cycle (for instance, at the nucleus in interphase and the centromeres in prometaphase of mitosis). We show that Aurora B phosphorylates p53 at S183, T211, and S215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and PUMA). Pharmacologic inhibition of Aurora B in cancer cells with WT p53 increased p53 protein level and expression of p53 target genes to inhibit tumor growth. Together, these results define a mechanism of p53 inactivation during the cell cycle and imply that oncogenic hyperactivation or overexpression of Aurora B may compromise the tumor suppressor function of p53. We have elucidated the antineoplastic mechanism for Aurora B kinase inhibitors in cancer cells with WT p53.