Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency.

Transcription factor Stat3 directs self-renewal of pluripotent mouse embryonic stem (ES) cells downstream of the cytokine leukemia inhibitory factor (LIF). Stat3 upregulates pivotal transcription factors in the ES cell gene regulatory network to sustain naïve identity. Stat3 also contributes to the rapid proliferation of ES cells. Here, we show that Stat3 increases the expression of mitochondrial-encoded transcripts and enhances oxidative metabolism. Chromatin immunoprecipitation reveals that Stat3 binds to the mitochondrial genome, consistent with direct transcriptional regulation. An engineered form of Stat3 that localizes predominantly to mitochondria is sufficient to support enhanced proliferation of ES cells, but not to maintain their undifferentiated phenotype. Furthermore, during reprogramming from primed to naïve states of pluripotency, Stat3 similarly upregulates mitochondrial transcripts and facilitates metabolic resetting. These findings suggest that the potent stimulation of naïve pluripotency by LIF/Stat3 is attributable to parallel and synergistic induction of both mitochondrial respiration and nuclear transcription factors.GM’s laboratory is supported by grants from Armenise-Harvard Foundation and Telethon Foundation (TCP13013). The Cambridge Stem Cell Institute receives core funding from the Wellcome Trust and Medical Research Council. GM was supported by a Human Frontier Science Program Fellowship. AS is a Medical Research Professor.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.15252/embj.20159262

The transcriptional regulator ZNF398 mediates pluripotency and epithelial character downstream of TGF-beta in human PSCs

Human pluripotent stem cells (hPSCs) have the capacity to give rise to all differentiated cells of the adult. TGF-beta is used routinely for expansion of conventional hPSCs as flat epithelial colonies expressing the transcription factors POU5F1/OCT4, NANOG, SOX2. Here we report a global analysis of the transcriptional programme controlled by TGF-beta followed by an unbiased gain-of-function screening in multiple hPSC lines to identify factors mediating TGF-beta activity. We identify a quartet of transcriptional regulators promoting hPSC self-renewal including ZNF398, a human-specific mediator of pluripotency and epithelial character in hPSCs. Mechanistically, ZNF398 binds active promoters and enhancers together with SMAD3 and the histone acetyltransferase EP300, enabling transcription of TGF-beta targets. In the context of somatic cell reprogramming, inhibition of ZNF398 abolishes activation of pluripotency and epithelial genes and colony formation. Our findings have clear implications for the generation of bona fide hPSCs for regenerative medicine

a propensity score analysis exploring the impact of the addition of adjuvant chemotherapy act to hormone therapy aht in a multi center series of resected luminal early stage pure invasive lobular breast carcinoma ilc

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PO-502 A potential role for HSP90 in HER2-driven breast cancer (BC)

Introduction HER2 (amplified in 30% of BC) is involved in the activation of many pathways and its function is regulated by HSP90. Thus, HSP90 co-targeting is emerging as a potential molecular target for HER2-directed BC therapy. Material and methods We analysed HER2 and HSP90 expression in a panel of BC cell lines, including MCF7 cells stably transfected with a constitutively active HER2. HER2/HSP90 expression and growth inhibition were monitored over time upon exposure to trastuzumab (T) and docetaxel (D), in the presence or absence of HSP90 silencing. We also retrospectively evaluated a series of 24 locally advanced/operable BC patients (pts) who underwent neoadjuvant T+D for HSP90 expression and correlated it with pathological complete response (pCR). Results and discussions In the BC cell lines analysed there was no clear-cut correlation between HSP90 and HER2 expression. HER2 transfection into MCF7 cells increased HSP90 mRNA and protein expression; however, treatment with T further increased HSP90 levels. Conversely D increased HER2, but did not affect HSP90, expression. In HER2 +BC cell lines, simultaneous T+D combination resulted in synergistic growth inhibition in vitro , while their staggered combination, particularly T followed by D, did not afford synergistic effects. Effects of simultaneous and staggered treatments on HSP90 and HER2 expression were analysed by WB: HER2 expression decreased in the simultaneous and staggered combination (D followed by T), while HSP90 expression did not change upon combined treatment. The effects of HSP90 silencing and overexepression on functional response to T+D are being analysed in HER2 +BC models: preliminary results indicate that HSP90 silencing in HER2 +BC decreases the therapeutic synergism of the simultaneous T+D combination. Accordingly, in locally advanced/operable pts undergoing neoadjuvant T+D, pCR occurred more frequently in pts with a baseline HSP90 score of 3+, as compared to 2+and 1+ (50.0% vs. 14.3% vs. none, p=0.05). These results suggest the possibility to classify HER2-positive pts into HSP90 defined subgroups and elaborate specific therapeutic strategies. Conclusion Preclinical data indicate that constitutive HER2 activation induces HSP90 expression and HSP90 modulation influences the functional response to combined treatment. Baseline HSP90 expression may potentially represent a pre-requisite of pharmacological response in HER2-addicted BC

Incorporating weekly carboplatin in anthracycline and paclitaxel-containing neoadjuvant chemotherapy for triple-negative breast cancer: propensity-score matching analysis and TIL evaluation

Background The generation of data capturing the risk-benefit ratio of incorporating carboplatin (Cb) to neoadjuvant chemotherapy (NACT) for triple-negative breast cancer (TNBC) in a clinical practice setting is urgently needed. Tumour-infiltrating lymphocytes (TILs) have an established role in TNBC receiving NACT, however, the role of TIL dynamics under NACT exposure in patients receiving the current standard of care is largely uncharted. Methods Consecutive TNBC patients receiving anthracycline-taxane [A-T] +/- Cb NACT at three Institutions were enrolled. Stromal-TILs were evaluated on pre-NACT and residual disease (RD) specimens. In the clinical cohort, propensity-score-matching was used to control selection bias. Results In total, 247 patients were included (A-T = 40.5%, A-TCb = 59.5%). After propensity-score-matching, pCR was significantly higher for A-TCb vs A-T (51.9% vs 34.2%, multivariate: OR = 2.40, P = 0.01). No differences in grade >= 3 haematological toxicities were observed. TILs increased from baseline to RD in the overall population and across A-T/A-TCb subgroups. TIL increase from baseline to RD was positively and independently associated with distant disease-free survival (multivariate: HR = 0.43, P = 0.05). Conclusions We confirmed in a clinical practice setting of TNBC patients receiving A-T NACT that the incorporation of weekly Cb significantly improved pCR. In addition, A-T +/- Cb enhanced immune infiltration from baseline to RD. Finally, we reported a positive independent prognostic role of TIL increase after NACT exposure

preliminary results of principe predictors of resistance to immunotherapy with nivolumab niv study in advanced pretreated non small cell lung cancer apnsclc investigating the role of an immune genomic signature igs including jak2 jak3 pias4 ptpn2 stat3 ifnar2 alterations

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Real-world ANASTASE study of atezolizumab+nab-paclitaxel as first-line treatment of PD-L1-positive metastatic triple-negative breast cancer

The combination of atezolizumab and nab-paclitaxel is recommended in the EU as first-line treatment for PD-L1-positive metastatic triple-negative breast cancer (mTNBC), based on the results of phase III IMpassion130 trial. However, ‘real-world’ data on this combination are limited. The ANASTASE study (NCT05609903) collected data on atezolizumab plus nab-paclitaxel in PD-L1-positive mTNBC patients enrolled in the Italian Compassionate Use Program. A retrospective analysis was conducted in 29 Italian oncology centers among patients who completed at least one cycle of treatment. Data from 52 patients were gathered. Among them, 21.1% presented de novo stage IV; 78.8% previously received (neo)adjuvant treatment; 55.8% patients had only one site of metastasis; median number of treatment cycles was five (IQR: 3–8); objective response rate was 42.3% (95% CI: 28.9–55.7%). The median time-to-treatment discontinuation was 5 months (95% CI: 2.8–7.1); clinical benefit at 12 months was 45.8%. The median duration of response was 12.7 months (95% CI: 4.1–21.4). At a median follow-up of 20 months, the median progression-free survival was 6.3 months (95% CI: 3.9–8.7) and the median time to next treatment or death was 8.1 months (95% CI: 5.5–10.7). At 12 months and 24 months, the overall survival rates were 66.3% and 49.1%, respectively. The most common immune-related adverse events included rash (23.1%), hepatitis (11.5%), thyroiditis (11.5%) and pneumonia (9.6%). Within the ANASTASE study, patients with PD-L1-positive mTNBC treated with first-line atezolizumab plus nab-paclitaxel achieved PFS and ORR similar to those reported in the IMpassion130 study, with no unexpected adverse events

Flood Protection in Venice under Conditions of Sea-Level Rise: An Analysis of Institutional and Technical Measures

It is widely acknowledged that in times of climate change loss of coastal resources and risk for human life can be minimized by implementing adaptation strategies. Such strategies need to encompass a balanced mix of non-structural (institutional) and structural (technical) measures based on sound scientific knowledge. This article discusses measures carried out to protect the city of Venice, Italy from flooding (locally known as “high water”), and reflects on their ability to anticipate a possible acceleration of sea-level rise as induced by climate change. It is based on scientific literature, legislative and policy documents of key institutions, reports and documents of organizations working on Venice issues, newspaper articles, and interviews. Our analysis shows that the synergic action of the hydraulic defense infrastructure under construction is in principle adequate to withstand a broad range of sea-level rise scenarios for the next 100 years. However, when the goal is to use these investments effectively major changes in the existing institutional arrangements will be required in the years to come. The Venice findings point out the difficulties and yet the importance of identifying and implementing both non-structural and structural measures to adapt to climate change

Palbociclib plus fulvestrant or everolimus plus exemestane for pretreated advanced breast cancer with lobular histotype in er+/her2 12 patients: A propensity score-matched analysis of a multicenter retrospective patient series

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) show meaningful efficacy and tolerability in patients with metastatic breast cancer (MBC), but the optimal sequence of ET has not been established. It is not clear if patients with lobular breast carcinomas (LBC) derive the same benefits when receiving second line CDK4/6i. This retrospective study compared the efficacy of palbociclib plus fulvestrant (PALBO\u2013FUL) with everolimus plus exemestane (EVE\u2013EXE) as second-line ET for hormone-resistant metastatic LBC. From 2013 to 2018, patients with metastatic LBC positivity for estrogen and/or progesterone receptors and HER2/neu negativity, who had relapsed during adjuvant hormonal therapy or first-line hormonal treatment, were enrolled from six centers in Italy in this retrospective study. A total of 74 out of 376 patients (48 treated with PALBO\u2013FUL and 26 with EVE\u2013EXE) with metastatic LBC were eligible for inclusion. Progression-free survival (PFS) was longer in patients receiving EVE\u2013EXE compared with PALBO\u2013FUL (6.1 vs. 4.5 months, univariate HR 0.58, 95% CI 0.35\u20130.96; p = 0.025). On the propensity score (PS) analysis, PFS was confirmed to be significantly longer for patients treated with EVE\u2013EXE compared to PALBO\u2013FUL (6.0 vs. 4.6 months, p = 0.04). This retrospective analysis suggests that EVE\u2013EXE is more effective than PALBO\u2013FUL for second line ET of metastatic LBC, allowing us to speculate on the optimal therapeutic sequence