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Mutant TP53 proteins are thought to drive the development and sustained expansion of cancers at least in part through the loss of the wild-type (wt) TP53 tumour suppressive functions. Therefore, compounds that can restore wt TP53 functions in mutant TP53 proteins are expected to inhibit the expansion of tumours expressing mutant TP53. APR-246 has been reported to exert such effects in malignant cells and is currently undergoing clinical trials in several cancer types. However, there is evidence that APR-246 may also kill malignant cells that do not express mutant TP53. To support the clinical development of APR-246 it is important to understand its mechanism(s) of action. By establishing isogenic background tumour cell lines with different TP53/TRP53 states, we found that APR-246 can kill malignant cells irrespective of their TP53/TRP53 status. Accordingly, RNAseq analysis revealed that treatment with APR-246 induces expression of the same gene set in Eμ-Myc mouse lymphoma cells of all four possible TRP53 states, wt, wt alongside mutant, knockout and knockout alongside mutant. We found that depending on the type of cancer cell and the concentration of APR-246 used, this compound can kill malignant cells through induction of various programmed cell death pathways, including apoptosis, necroptosis and ferroptosis. The sensitivity of non-transformed cells to APR-246 also depended on the cell type. These findings reveal that the clinical testing of APR-246 should not be limited to cancers expressing mutant TP53 but expanded to cancers that express wt TP53 or are TP53-deficient.

Cell death, cell cycle arrest and cellular senescence are three distinct cellular responses that can be induced by oncogene activation and diverse anti-cancer agents, and this often requires the action of the tumour suppressor TP53. Within a cell population, or even within an individual cell, these processes are not necessarily mutually exclusive. It is therefore important to measure all these processes simultaneously. However, current assays generally visualise only one or at best two responses, often only detecting the dominant one. Here, we present a novel flow cytometric assay that allows simultaneous assessment of cell viability and cell cycling through measurement of DNA content and DNA synthesis, and markers of cell senescence at the single cell level. We demonstrate that this assay can be performed on both human and murine cells, that are either cancerous or non-transformed, and can help to dissect complex cell fate decisions. We believe that this experimental tool will be useful for the study of diverse biological processes.

Mutant TP53 proteins are thought to drive the development and sustained expansion of cancers at least in part through the loss of the wild-type (wt) TP53 tumour suppressive functions. Therefore, compounds that can restore wt TP53 functions in mutant TP53 proteins are expected to inhibit the expansion of tumours expressing mutant TP53. APR-246 has been reported to exert such effects in malignant cells and is currently undergoing clinical trials in several cancer types. However, there is evidence that APR-246 may also kill malignant cells that do not express mutant TP53. To support the clinical development of APR-246 it is important to understand its mechanism(s) of action. By establishing isogenic background tumour cell lines with different TP53/TRP53 states, we found that APR-246 can kill malignant cells irrespective of their TP53/TRP53 status. Accordingly, RNAseq analysis revealed that treatment with APR-246 induces expression of the same gene set in Em-Myc mouse lymphoma cells of all four possible TRP53 states, wt, wt alongside mutant, knockout and knockout alongside mutant. We found that depending on the type of cancer cell and the concentration of APR-246 used, this compound can kill malignant cells through induction of various programmed cell death pathways, including apoptosis, necroptosis and ferroptosis. The sensitivity of non-transformed cells to APR-246 also depended on the cell type. These findings reveal that the clinical testing of APR-246 should not be limited to cancers expressing mutant TP53 but expanded to cancers that express wt TP53 or are TP53-deficient.

This exploratory study examined the extent to which coping, resilience, experiences of subtle and blatant racism, and ethnic identity predicted stress-related growth in a national convenience sample of Asians and Asian Americans and Pacific Islanders (AAPIs; N = 326) who experienced COVID-19–related racial discrimination. Our analysis indicated participants with higher levels of coping, resilience, experiences of subtle and blatant racism, and ethnic identity were significantly more likely to cultivate higher levels of stress-related growth. Coping strategies such as self-blame, religion, humor, venting, substance use, denial, and behavioral disengagement significantly moderated the relationship between experiences of racism and stress-related growth. Notably, participants in the study who used mental health services following COVID-19 reported significantly higher levels of racial discrimination, resilience, coping, and stress-related growth compared to Asians and AAPIs who did not use professional mental health services. Mental health professionals are called to utilize culturally sensitive treatment modalities and challenge traditional Western notions that frame coping responses from an individualistic worldview.

Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are individually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones.

Universities and colleges worldwide have quickly moved campus-based classes to virtual spaces due to the COVID-19 pandemic. This article explores the impact of this sudden transition of learning an...

The appeal of revolutionising urban governance through information technologies has prompted cities across the globe to pursue smart city initiatives. The mainstream scholarship on these initiatives has mostly focused on technology and corporate-led urban development, and it also often privileges the experience of cities in the global North. Nevertheless, this mainstream understanding of the smart city may obscure emerging new power dynamics and locally contextualised processes associated with smart urban development, especially in cities at the global periphery. Inspired by post-colonial theories, this article makes the case for ‘provincialising’ smart urbanism by dislodging technology from the centre of analysis, accentuating perspectives of cities outside the locations where the smart city knowledge is traditionally produced and attending to power relationships. In our case study of Taipei, this provincialising approach helps unveil various logics, intentionalities, assemblages and power dynamics through which the smart city is employed as a political strategy to facilitate urban regime transition. We argue that the current non-affiliated Ko administration exploits the veneer of technological superiority and political neutrality of its smart city agenda to set a new growth agenda, form new development coalitions, establish new institutions and incorporate rising populist momentum into policy-making. Focusing on the politics of being smart, our findings illustrate how smart city experiments reshape power dynamics and regime formation through reorganising actors and interest groups, reconfiguring government institutions, reallocating resource distribution and, in the end, bolstering governing legitimacy.

Background Simulation-based Helping Babies Breathe (HBB) training is currently rolled-out in around 80 low-income countries with various results. Method Workflow was analyzed in 76 video-recorded newborn resuscitations performed by regularly HBB-trained nurse-midwives over 3 years in rural Tanzania. Results Actual newborn resuscitation practice deviated from HBB intention/guideline: most newborns underwent prolonged suction and stimulation before ventilation; ventilation was delayed and frequently interrupted. Nurse-midwives often worked together. Conclusions There is a gap between training intention and clinical practice. HBB trainings should focus more on urgency, ventilation skills, and team training. Combining clinical debriefing with HBB simulations could facilitate continuous learning and application.

Dysregulated expression of BCL-2 family proteins allows cancer cells to escape apoptosis. To counter this, BH3-mimetic drugs that target and inhibit select BCL-2 prosurvival proteins to induce apoptosis have been developed for cancer therapy. Venetoclax, which targets BCL-2, has been effective as therapy for patients with chronic lymphocytic leukemia, and MCL-1–targeting BH3-mimetic drugs have been extensively evaluated in preclinical studies for a range of blood cancers. Recently, BCL-W, a relatively understudied prosurvival member of the BCL-2 protein family, has been reported to be abnormally upregulated in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma patient samples. Therefore, to determine if BCL-W would be a promising therapeutic target for B-cell lymphomas, we have examined the role of BCL-W in the sustained growth of human BL- and DLBCL-derived cell lines. We found that CRISPR/CAS9-mediated loss or short hairpin RNA-mediated knockdown of BCL-W expression in selected BL and DLBCL cell lines did not lead to spontaneous apoptosis and had no effect on their sensitivity to a range of BH3-mimetic drugs targeting other BCL-2 prosurvival proteins. Our results suggest that BCL-W is not universally required for the sustained growth and survival of human BL and DLBCL cell lines. Thus, targeting BCL-W in this subset of B-cell lymphomas may not be of broad therapeutic benefit.

BackgroundHeart rate (HR) is used to guide interventions during delivery room (DR) neonatal resuscitation. Dry electrode ECG (NeoBeat) may detect HR more rapidly than pulse oximetry (PO) and portable ECG, but real-time comparisons of these devices are lacking.Design/methodsPO, ECG and NeoBeat were placed sequentially on newborns in the DR. Time for device placement and time to accurate HR acquisition were noted.ResultsDR resuscitations of 28 preterm/term infants were observed. The NeoBeat was placed faster (ie, 3 s) than PO (20 s, p=ConclusionsThese observations in a small cohort of relatively well neonates demonstrate that the NeoBeat is significantly faster to place and consistently acquires HR faster than PO and ECG.

Umm Ghudair Field is one of the major oil producing fields in West Kuwait. Oil was discovered in 1962 in the Lower Cretaceous Minagish Oolite Formation and more than 200 wells have been drilled to exploit this reservoir since then. Stratigraphically, the formation is defined by three units; Lower, Middle and Upper. The lower and upper units are considered non-reservoirs, while the middle one is hydrocarbon bearing. However, because of the continuous production over the past 50 years, the filed started to show a variable rise in its oil water contact (OWC). Consequently, this uncertain OWC rise has impacted the planning and production of the newly drilled wells (deviated and horizontal). Several recently drilled wells showed water breakthrough much earlier than expected. To address this challenge and with an attempt to proactively predict the current OWC depth in the new wells to be drilled, Kuwait Oil Company (KOC) decided to try the new High Definition Reservoir-Mapping-While-Drilling (HD-RMWD) technology in one of the horizontal well in their field. The objective was to assess the potential of the technology in detecting and mapping the current OWC while landing the well in the target. Due to the ultra-deep detection range of the technology (in excess of 200 ft), the landing point could be adjusted proactively and early enough to accommodate any unexpected OWC depth changes in the field.

Polycystic ovarian syndrome (PCOS) is a leading cause of infertility among women of reproductive age. The interplay between hyperinsulinemia and obesity results in many of the reproductive and hormonal changes seen in PCOS including abnormal menses, infertility, and pregnancy loss. While bariatric surgery has been found to be an effective treatment strategy for morbid obesity, its role in the management of PCOS-related infertility compared to standard therapy (metformin) is less clear. To assess the impact of bariatric surgery on pregnancy outcomes in women with PCOS compared to metformin therapy in a systematic review and meta-analysis. MEDLINE, EMBASE, PubMed, and Google Scholar were searched from inception to August 2019. Studies that reported quantitative data on pregnancy outcomes on women of reproductive age with PCOS with at least a 3-month follow-up and a minimum of 5 or more sample size were included. The primary outcome was pregnancy rate, expressed as an event rate and 95% confidence interval (95% CI). Ten studies with a total of 587 patients were included in the final analyses (Metformin: 5 studies, n = 192; Bariatric surgery (BS): 5 studies (2 Roux-en-Y gastric bypass, 2 sleeve gastrectomy, 1 Roux-en-Y gastric bypass + sleeve gastrectomy), n = 186). The average time to follow-up was 18.25 months (range 3–36) with a shorter time to follow-up in the metformin group compared to the bariatric surgery group (Metformin: 11.2 vs BS: 24.5 months). While metformin increased the likelihood of pregnancy compared to placebo or non-surgical interventions (OR = 3.08, 95% CI 1.29–7.37, p = 0.01), the pregnancy rate after bariatric surgery was greater than metformin (34.9%, 95% CI 0.20–0.53 vs 17.1%, 95% CI 0.12–0.23, p = 0.026 for the difference). Additionally, there was a trend to a greater improvement in menstrual irregularity in the bariatric group compared to the metformin group with a reduction of 92% in the bariatric cohort compared to a reduction of 54% in the metformin cohort, but the data was limited. Bariatric surgery appears to be a more effective treatment strategy for patients with PCOS and class 3 obesity compared to metformin alone. Women with PCOS and infertility should consider bariatric surgery for weight loss and improvement in pregnancy outcomes.

The immediate delivery room (DR) management of non-vigorous (NV) infants with meconium stained amniotic fluid (MSAF) is controversial. A recent ILCOR suggestion is not to perform routine direct laryngoscopy (DL) with or without tracheal suctioning in NV infants. Our practice is to perform DL and endotracheal (ET) suctioning in targeted NV infants. The study objective was to describe the perinatal characteristics and DR Management of infants born through MSAF and admitted to the neonatal intensive care unit (NICU). Methods Retrospective study evaluating the DR management of infants >35 weeks delivered through MSAF. Data retrieved included fetal heart rate abnormalities (FTHR), presence of thick/thin MSAF, DR management and postnatal course. Results 118 infants were resuscitated and directly admitted to the NICU, including 58 intubated for meconium, 29 receiving immediate PPV (n = 25) or CPAP (n = 4) and 31 (17%) initially stable developed delayed respiratory symptoms and administered CPAP. Sixty-four (35.2%) infants initially stable in the DR were subsequently admitted to NICU. ET suctioning was performed in 58/182 infants with meconium obtained in 41/58; meconium aspiration syndrome (MAS) was diagnosed in 21 infants. ET suctioning was positive in 10/21 cases. FHRT abnormalities (n = 50) were noted with thick meconium and associated with a 2.8-fold increased risk for meconium below the cords, and 3.1-fold increased risk of MAS. Conclusion NV infants delivered through thick versus thin meconium were more likely to be intubated with a high yield of recovery. Serious pulmonary morbidity was uncommon. Most respiratory symptomatology were not related to MAS.

Epstein-Barr virus (EBV)–associated T- and natural killer (NK)–cell malignancies, such as extranodal NK-/T-cell lymphoma (ENKTL), exhibit high chemoresistance and, accordingly, such patients have a poor prognosis. The rare nature of such cancers and nonmalignant T/NK lymphoproliferative disorders, such as chronic active EBV (CAEBV), has limited our understanding of the pathogenesis of these diseases. Here, we characterize a panel of ENKTL- and CAEBV-derived cell lines that had been established from human tumors to be used as preclinical models of these diseases. These cell lines were interleukin-2 dependent and found to carry EBV in a latency II gene-expression pattern. All cell lines demonstrated resistance to cell death induction by DNA damage–inducing agents, the current standard of care for patients with these malignancies. This resistance was not correlated with the function of the multidrug efflux pump, P-glycoprotein. However, apoptotic cell death could be consistently induced following treatment with A-1331852, a BH3-mimetic drug that specifically inhibits the prosurvival protein BCL-XL. A-1331852–induced apoptosis was most efficacious when prosurvival MCL-1 was additionally targeted, either by BH3-mimetics or genetic deletion. Xenograft models established from the ENKTL cell line SNK6 provided evidence that A-1331852 treatment could be therapeutically beneficial in vivo. The data here suggest that therapeutic targeting of BCL-XL would be effective for patients with EBV-driven T/NK proliferative diseases, however, MCL-1 could be a potential resistance factor.

* Abbreviations: COVID-19 — : coronavirus disease 2019 CPAP — : continuous positive airway pressure DR — : delivery room PI — : premature infant PPE — : personal protective equipment PUI — : patient under investigation SARS-CoV-2 — : severe acute respiratory syndrome coronavirus 2 WBN — : well-baby nursery Since the initial report of a novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan in December 2019, there has been widespread dissemination of disease worldwide.1 The impact on the neonatal population has been reported almost exclusively from China.2–8 Our study goal is to characterize for the first time in the United States the delivery room (DR) management and early course of infants born to mothers positive for coronavirus disease 2019 (COVID-19) during 3 weeks at the peak of the pandemic in New York, New York, and to describe the challenges and approaches developed to meet these excessive needs. This is a prospective initiative of mothers admitted to labor and delivery, all of whom were tested, and is focused on those who tested positive for COVID-19 via SARS-CoV-2 polymerase chain reaction obtained from a nasopharyngeal swab only and their infants triaged to the well-baby nursery (WBN) or admitted to NICU at New York-Presbyterian Hospital Weill Cornell Medicine between March 22 and April 15th, 2020. A checklist developed during the process delineated DR … Address correspondence to Jeffrey Perlman, MB, ChB, Division of Newborn Medicine, Department of Pediatrics, 525 E 68th St, Suite N-506, New York, NY 10065. E-mail: jmp2007{at}med.cornell.edu

The tumour suppressor TP53 is the most frequently mutated gene in human cancer and these aberrations confer poor chemotherapeutic responses1-3. Point mutations typically cluster in the DNA binding domain, with certain ‘hot-spot’ residues disproportionally represented1-4 These mutations abrogate binding of the TP53 transcription factor to DNA and thereby prevent upregulation of genes critical for tumour suppression (loss-of-function)1-3. Mutant TP53 is reported to additionally contribute to tumour development, sustained growth and metastasis not only through dominant-negative effects on wild-type TP535 but also through neomorphic gain-of-function (GOF) activities6. Understanding the contributions of these postulated attributes of mutant TP53 to the development and expansion of tumours will facilitate the design of rational therapeutic strategies. Here we used CRISPR/CAS9 to delete mutant TP53 in a panel of diverse human cancer cell lines. The loss of mutant TP53 expression had no impact on the survival, proliferative capacity or metabolic state of the tumour cells, nor did it sensitise them to cellular stresses and chemotherapeutic agents. These data suggest that putative GOF effects of mutant TP53 are not universally required for the sustained survival and proliferation of fully malignant cells. Therefore, therapeutic approaches that abrogate expression or function of mutant TP53 would not be expected to have substantial impact.

The core features of schizophrenia (SCZ) include cognitive deficits and impaired sensory gating represented by P50 inhibition deficits, which appear to be related to the α7 nicotinic acetylcholine receptor (nAChR). An agonist of nAChR receptor may improve these defects. This study aimed to investigate how administering multiple doses of tropisetron, a partial agonist of nAChR, for 1 day would affect cognitive deficits and P50 inhibition deficits in SCZ patients. We randomized 40 SCZ non-smokers into a double-blind clinical trial with four groups: placebo, 5 mg/d, 10 mg/d, and 20 mg/d of oral tropisetron. Their P50 ratios were all more than 0.5 and they took risperidone at 3–6 mg/day for at least a month before participating in the experiment. We measured the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and P50 inhibition before and one day after treatment. After one day of treatment, the total RBANS scores of the 20 mg and 5 mg tropisetron groups, and the immediate memory of the 10 mg group were significantly higher than placebo group. The P50 ratio was smaller in the 5 mg and 10 mg groups than in the placebo group (both p

To compare sublobar resection and stereotactic body radiation therapy (SBRT) in patients with stage I non-small cell lung cancer (NSCLC).Patients undergoing sublobar resection or SBRT for stage I NSCLC from 2007 to 2014 at Duke University Medical Center were evaluated. The primary endpoint of interest was freedom from local recurrence. Kaplan-Meier survival estimates and Cox proportional hazards multivariate analyses were performed.221 patients with stage I NSCLC undergoing sublobar resection (n = 151; 105 wedge and 46 segmentectomy) or SBRT (n = 70) were evaluated. The majority (89%) of patients receiving SBRT were medically inoperable, and compared with surgical patients, were significantly older (74 vs 70 years, p = 0.019), had higher Charlson Comorbidity Indices (3.7 vs 2.7, p 0.001), larger tumors (2.4 cm vs 1.7 cm, p 0.001), and worse baseline pulmonary function. At 3 years, freedom from local recurrence was 90% (95% CI 82-94%) for surgery and 85% (95% CI 65-94%) for SBRT (p = 0.71). While overall survival and disease-free survival were higher in the surgical cohort, no differences were noted in cancer-specific disease-free survival (60% vs. 65%, p = 0.84). On multivariate analysis, higher Charlson Comorbidity Index (HR 1.38, 95% CI 1.19-1.61, p 0.001) and lower diffusion capacity (HR 0.97, 95% CI 0.96-0.98, p 0.001) were independently associated with inferior overall survival. No differences in overall survival between surgery and SBRT (HR 1.20, 95% CI 0.74-1.95, p = 0.46) were observed after correcting for baseline imbalances in prognostic factors.SBRT and sublobar resection provided similar rates of local tumor control and overall clinical outcomes in stage I NSCLC.

Myeloid cell leukemia-1 (MCL-1) is a prosurvival B-cell lymphoma 2 (BCL-2) family member required for the sustained growth of many cancers. Recently, a highly specific MCL-1 inhibitor, S63845, showing sixfold higher affinity to human compared with mouse MCL-1, has been described. To accurately test efficacy and tolerability of this BH3-mimetic (BH3-only protein mimetic) drug in preclinical cancer models, we developed a humanized Mcl-1 (huMcl-1) mouse strain in which MCL-1 was replaced with its human homolog. huMcl-1 mice are phenotypically indistinguishable from wild-type mice but are more sensitive to the MCL-1 inhibitor S63845. Importantly, nontransformed cells and lymphomas from huMcl-1;Eµ-Myc mice are more sensitive to S63845 in vitro than their control counterparts. When huMcl-1;Eµ-Myc lymphoma cells were transplanted into huMcl-1 mice, treatment with S63845 alone or alongside cyclophosphamide led to long-term remission in ∼60% or almost 100% of mice, respectively. These results demonstrate the potential of our huMcl-1 mouse model for testing MCL-1 inhibitors, allowing precise predictions of efficacy and tolerability for clinical translation.

Highlights • ASCIZ/ATMIN is not required for ATM activation by replication stress in MEFs. • ATM activation is normal in human ASCIZ/ATMIN KO cells. • ASCIZ/ATMIN is dispensable for aphidicolin-induced 53BP1 focus formation., The ATM kinase plays critical roles in the response to DNA double-strand breaks, and can also be activated by prolonged DNA replication blocks. It has recently been proposed that replication stress-dependent ATM activation is mediated by ASCIZ (also known as ATMIN, ZNF822), an essential developmental transcription factor. In contrast, we show here that ATM activation, and phosphorylation of its substrates KAP1, p53 and H2AX in response to the replication blocking agent aphidicolin was unaffected in both immortalized and primary ASCIZ/ATMIN-deficient murine embryonic fibroblasts compared to control cells. Similar results were also obtained in human ASCIZ/ATMIN-deleted lymphoma cells. The results demonstrate that ASCIZ/ATMIN is dispensable for ATM activation, and contradict the previously reported dependence of ATM on ASCIZ/ATMIN.

A 56-year-old G3P3 postmenopausal woman presented with a 5 month history of abnormal uterine bleeding and pelvic pain. A computed tomographic scan revealed a 5 cm right adnexal cystic mass in addition to a thickened, heterogenous endometrium and leiomyomatous uterus. A total laparascopic hysterectomy and bilateral salpingo-oophorectomy with omental and peritoneal biopsy were performed. Gross examination revealed a 12 week size uterus with small fibroids, normal bilateral atrophic ovaries, and a right paratubal cyst. A 4 cm vegetating mass was found in the right side of the uterine wall. Microscopically, the uterine mass was diagnosed as an endometrioid adenocarcinoma (EAC) FIGO 1 with 70% of myometrial invasion. The remaining endometrium showed a complex atypical hyperplasia. In addition, a 5 cm paratubal cystic mass was found that was separate from the uterus and the right adnexa. The cyst content was a chocolate brown fluid and the cyst wall was smooth with a single solid mass of 2 cm in size. The diagnosis of EAC, FIGO 1 was given. The remaining cyst lining showed endometriotic cyst and foci of endometriosis in the cyst wall. There was no lymphovascular invasion. The entire fallopian tube and ovaries were submitted and they were free of tumor. The patient was diagnosed with primary EAC of the paratubal cyst in addition to EAC of the uterine corpus (pT1b). A close follow-up was recommended. Because of our limited knowledge of carcinomas arising in the paratubal cyst, we will review the literature and discuss their clinical aspects, management, and behavior.

This paper is an attempt to reassess the role of failure in policy mobilities. Empirically, this paper examines the various aftermaths of, and the continuing trans-local connections originating from, the prominent but un-materialized Sino-British Shanghai-Dongtan eco-city—with a particular consideration on its relation with a subsequently realized project—the Sino-Singapore Tianjin eco-city. The findings reveal that despite its apparent failure, Dongtan eco-city established a set of urban planning procedures adopted by many, including those who designed and delivered the Tianjin eco-city. Meanwhile, Dongtan’s failure to materialize motivated the Chinese government to pursue collaboration with the Singaporean government over the increased involvement of private Western partners. The intent to avoid association with Dongtan’s failure also fostered a new eco-urbanism model based on rebranding the planning practices of Singapore’s public housing. Parts of Dongtan eco-city have also lived on through the international circulation of a piece of planning software that was first developed for the failed project. This paper contributes to the policy mobilities literature by challenging its dominant focus on successful exemplars and exploring how a project fails in implementation yet parts of it remain mobile, influential and present in other developments. This paper also advances the understanding of contemporary urban sustainability by revealing how eco-urbanism models are co-produced in this globalizing era between the global North and South, as well as within the global South.

Epstein–Barr virus (EBV), which is ubiquitous in the adult population, is causally associated with human malignancies. Like many infectious agents, EBV has evolved strategies to block host cell death, including through expression of viral homologues of cellular BCL-2 pro-survival proteins (vBCL-2s), such as BHRF1. Small molecule inhibitors of the cellular pro-survival BCL-2 family proteins, termed ‘BH3-mimetics’, have entered clinical trials for blood cancers with the BCL-2 inhibitor venetoclax already approved for treatment of therapy refractory chronic lymphocytic leukaemia and acute myeloid leukaemia in the elderly. The generation of BH3-mimetics that could specifically target vBCL-2 proteins may be an attractive therapeutic option for virus-associated cancers, since these drugs would be expected to only kill virally infected cells with only minimal side effects on normal healthy tissues. To achieve this, a better understanding of the contribution of vBCL-2 proteins to tumorigenesis and insights into their biochemical functions is needed. In the context of Burkitt lymphoma (BL), BHRF1 expression conferred strong resistance to diverse apoptotic stimuli. Furthermore, BHRF1 expression in mouse haematopoietic stem and progenitor cells accelerated MYC-induced lymphoma development in a model of BL. BHRF1 interacts with the cellular pro-apoptotic BCL-2 proteins, BIM, BID, PUMA and BAK, but its capability to inhibit apoptosis could not be mapped solely to one of these interactions, suggesting plasticity is a key feature of BHRF1. Site-directed mutagenesis revealed a site in BHRF1 that was critical for its interaction with PUMA and blocking DNA-damage-induced apoptosis, identifying a potentially therapeutically targetable vulnerability in BHRF1.

Effective communication is the keystone in the management of delivery room emergencies. A clearly defined framework and “shared mental model” optimize team collaboration and are essential when anticipating and preparing for high-stakes emergent cases. This review defines a framework to build shared mental models using dialogue, pre-briefing, checklists, simulation, debriefing and structured feedback to maintain a cohesive high functioning team. Strategies to approach different emergency lead-times will be discussed, and case examples will be used to illustrate concepts outlined.

Over the last decade, China’s quest for sustainable development has spawned hundreds of urban sustainability projects. Most of these projects involve displacing original inhabitants to make room for newly constructed residential enclaves courting China’s new middle-class and international elites. Ostensibly, these are new forms of environmental gentrification and housing inequality that adhere to the “accumulation by dispossession” logic commonly seen in cities in the global South. Yet my research on the life transitions of both displaced villagers and new residents in two Chinese eco-city constructions suggests that displacement also leads to new, divergent pathways in individual social mobility. Drawing on on-site observation, interviews, and ethnographic work, I find that villagers relocated from the project construction sites experienced different resettlement trajectories and life transitions, often contingent upon their capacity in acquiring compensation in the form of new property rights. For some, displacement was the first step toward further wealth accumulation. Meanwhile, the newly arrived middle-class residents at the eco-cities were deprived of their original urban lives and social relations, compelled to adjust to the new cities’ lack of infrastructure and amenities. Further compounding their problem is the housing market slump right after their home purchases, which seriously restricted the spatial mobility of the residents. As sustainability projects becomes a prominent agenda in contemporary urban policies, the findings of this research highlight the need to consider the inequality implications, particularly how new developments affect individual social and spatial mobility.

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

Chang I-C. C., Leitner H. and Sheppard E. A green leap forward? Eco-state restructuring and the Tianjin–Binhai eco-city model. Regional Studies. China has experienced a remarkable explosion of designated eco-cities since the year 2000, with Tianjin–Binhai becoming the best-practice model. Embedded in broader political economic changes, shifting multi-scalar regimes of environmental governance have shaped this efflorescence. Applying eco-state restructuring, this paper argues that eco-city construction became a new strategic project after the 2000s, driven by central state-driven model cities and assessment initiatives. This also led to a very different kind of ‘best practice’ eco-city model: Tianjin–Binhai, a China–Singapore collaboration in which greenness is manufactured rather than adapted. Notwithstanding significant implementation problems, Tianjin–Binhai's status as best practice persists, raising questions about what it means to claim eco-city status.