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Abstract: CD37-directed antibody and cellular-based approaches have shown preclinical and promising early clinical activity. Naratuximab emtansine (Debio 1562; IMGN529) is an antibody-drug conjugate (ADC) incorporating an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload, with activity as a single agent and in combination with rituximab in patients with lymphoma. We studied naratuximab emtansine and its free payload in 54 lymphoma models, correlated its activity with CD37 expression, characterized two resistance mechanisms, and identified combination partners providing synergy. The activity, primarily cytotoxic, was more potent in B- than T-cell lymphoma cell lines. After prolonged exposure to the ADC, one diffuse large B-cell lymphoma (DLBCL) cell line developed resistance to the ADC due to the CD37 gene biallelic loss. After CD37 loss, we also observed upregulation of interleukin-6 (IL-6) and related transcripts. Recombinant IL-6 led to resistance. Anti-IL-6 antibody tocilizumab improved the ADC’s cytotoxic activity in CD37+ cells. In a second model, resistance was sustained by a PIK3CD activating mutation, with increased sensitivity to PI3Kδ inhibition and a functional dependence switch from MCL1 to BCL2. Adding idelalisib or venetoclax overcame resistance in the resistant derivative and improved cytotoxic activity in the parental cells. In conclusion, targeting B-cell lymphoma with the naratuximab emtansine showed vigorous antitumor activity as a single agent, which was also observed in models bearing genetic lesions associated with inferior outcomes, such as Myc Proto-Oncogene (MYC) translocations and TP53 inactivation or R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone) resistance. Resistant DLBCL models identified active combinations of naratuximab emtansine with drugs targeting IL-6, PI3Kδ, and BCL2.

ABSTRACT: Background: Chronic pain after breast cancer surgery, affecting 25%-60% of patients, significantly impacts the survivors’ quality of life. With improved survival rates, more individuals are experiencing this long-term complication. It is often overlooked that this chronic pain may stem from peripheral nerve injury, resulting in neuropathic pain characterized by burning sensations, electric shocks, and heightened sensitivity. Although neuropathic pain prevalence is reported at 24%-36% post-mastectomy, the data following breast-conserving surgery remain limited. This systematic review aimed to investigate the prevalence of neuropathic pain after breast-conserving surgery and its potential association with axillary procedures. Methods: The electronic databases, Medline, Embase, Web of Science and Cochrane Central, were searched. Inclusion criteria were defined to include studies reporting on the prevalence of neuropathic pain following breast-conserving surgery and exploring associations with axillary procedures. A meta-analysis was performed to compute a pooled prevalence rate. Results: Eight studies, covering 1,469 patients post-breast-conserving surgery, met the inclusion criteria. The meta-analysis revealed a pooled prevalence of 31% (95% confidence intervals [CI] 0.14-0.56) neuropathic pain among patients who underwent breast-conserving surgery. Six studies explored associations with axillary procedures; however, none suggested a correlation between axillary procedures and neuropathic pain after breast-conserving surgery. Conclusion: This systematic review and meta-analysis indicated a pooled prevalence of 31% neuropathic pain following breast-conserving surgery of, with confidence interval ranging from 14% to 56%. The review did not provide conclusive evidence to suggest correlations between axillary procedures and neuropathic pain after breast-conserving surgery.

International students have become one of the main populations in Australian universities. However, due to the COVID-19 pandemic, many international students decided to go to other countries and regions for their higher education due to the border control policies in Australia. Based on the social cognitive career and motivation theory, this study explored the motivations and reasons why Chinese postgraduate international students decided to return to Australia after the Australian government officially re-opened the border for on-campus and face-to-face education and why Chinese postgraduate international students decided to study in Australia instead of other countries, particularly during the COVID-19 pandemic. Based on the general inductive approach with semi-structured interviews, focus group activities, and member-checking interviews, 20 Chinese postgraduate international students' stories were captured. The findings indicated that financial, academic, and personal considerations are significant in the participants’ decision-making processes. The results will fill the research gaps and become a reference in international student mobilities, decisions, and decision-making processes of international students, particularly during the COVID-19 pandemic in the Australian university environment.

Summary: Background: In chronic obstructive pulmonary disease (COPD), vascular alterations have been shown to contribute to hypoxia and pulmonary hypertension, but the independent contribution of small vessel abnormalities to mortality remains unclear. Methods: We quantified artery and vein dimensions on computed tomography (CT) down to 0.2 mm. Small vessel volumes (

Background: Delayed post-hypoxic leukoencephalopathy (DPHL) is characterized by a biphasic clinical course, with complete recovery from coma to a fully conscious state lasting one to four weeks (lucid interval), followed by abrupt neurological deterioration as an indirect consequence of hypoxic events like carbon monoxide poisoning and narcotic drug overdose. To our best knowledge, there are no documented cases in literature of choreoathetosis and dementia following poppy-induced DPHL with 14-3-3 protein in cerebrospinal fluid (CSF). Case presentation: We report the case of a 70-year-old female who underwent cardiopulmonary resuscitation (CPR) due to overdose of homemade refined opium poppy paste two weeks prior to presentation. She presented a progressive cognitive decline, along with the development of apraxia and choreic movement affecting her tongue and bilateral upper and lower extremities. During the symptomatic phase, brain magnetic resonance imaging (MRI) showed bilateral symmetrical hyperintense signals mostly in central frontal, temporal, and parieto-occipital lobes in the diffusion weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences which are the characteristic findings of DPHL. CSF routine analysis, as well as toxicology screening, autoimmune and paraneoplastic encephalitis panels were negative, but the presence of 14-3-3 protein in the CSF was detected. With steroid therapy, hyperbaric oxygen therapy and symptomatic treatment, she experienced gradual improvement in cognition, motivation, and psychomotor function. Conclusion: DPHL represents a distinct form of encephalopathy characterized by unique clinical course and imaging features. It is the first report of DPHL with positive 14-3-3 protein in CSF. The potential of 14-3-3 protein as a biomarker for diagnosing DPHL and its ability to predict disease severity and prognosis warrants further research.

Objective: Isatuximab (Isa, anti-CD38 monoclonal antibody) is approved in combination with carfilzomib (K) and dexamethasone (d), for relapsed multiple myeloma (MM) patients (pts) after ≥1 prior therapy. Final progression free survival (PFS) analysis after 2 years showed mPFS of 35.65 mo (Isa-Kd) vs 19.15 mo (Kd). Here, we report the final overall survival (OS) from IKEMA planned 3 years after the primary PFS analysis. Methodology: Pts with 1−3 prior lines of therapy were randomized 3:2 to receive Isa-Kd (n=179) or Kd (n=123). Treatment (tx) was given until progressive disease, unacceptable toxicity, or pt wish. Safety was assessed in all treated pts. Results: As of 7 Feb 2023, 23.5% (Isa-Kd) and 5.7% (Kd) pts were on tx. Median follow-up: 56.61 mo. OS benefit was more in Isa-Kd pts (mOS was NR; [95% CI: 52.172−NR] vs 50.6 mo [95% CI: 38.932−NR]; HR: 0.855; nominal one-sided p=0.1836). Isa-Kd had longer TTNT vs Kd (median 43.99 vs 25.0 mo; nominal one-sided p=0.0002), as was PFS2 (median 47.18 vs 32.36 mo; nominal one-sided p=0.0035). The safety profiles were comparable to interim and final PFS analyses. Grade ≥3 TEAEs: 84.2% (Isa-Kd) vs 73.0% (Kd). Conclusion: This final OS analysis shows a meaningful trend for OS benefit with Isa-Kd vs Kd despite subsequent tx with anti-CD38 agents, introduction of tx with novel mechanism of action among further therapies, and the COVID-19 pandemic. Improvements in TTNT and PSF2 were observed and sustained PFS benefit still observed at PFS2. The Isa-Kd safety profile was consistent with previous analyses, supporting it as a standard-of-care therapy for relapsed MM pts.

Despite the increase in the number of blockchain-based Decentralized Autonomous Organizations (DAOs), there is no consensus on what constitutes a DAO. This paper provides an in-depth study of DAOs by analyzing their definitions, characteristics, and emerging developments. Existing definitions in the literature hardly recognize common functionalities and intermingle coded DAOs, DAO deployment platforms, and blockchain DAOs. We developed a comprehensive DAO definition by reviewing the literature and empirically analyzing 1,859 DAOs. The findings show that many DAOs were inactive and that a threshold of 20 tokenholders is a tipping point for DAOs to survive over time and maintain sustained levels of activity. Finally, based on an empirical analysis of 9,845 perceived DAOs, we identified the emerging development of off-chain voting. This emerging development challenges the autonomous nature of DAOs. We recommend further research to investigate the effect of governance structures on their long-term sustainability and viability for both on-chain and off-chain DAOs.

Summary: Background: Efficient biomarker discovery and clinical translation depend on the fast and accurate analytical output from crucial technologies such as multiplex imaging. However, reliable cell classification often requires extensive annotations. Label-efficient strategies are urgently needed to reveal diverse cell distribution and spatial interactions in large-scale multiplex datasets. Methods: This study proposed Self-supervised Learning for Antigen Detection (SANDI) for accurate cell phenotyping while mitigating the annotation burden. The model first learns intrinsic pairwise similarities in unlabelled cell images, followed by a classification step to map learnt features to cell labels using a small set of annotated references. We acquired four multiplex immunohistochemistry datasets and one imaging mass cytometry dataset, comprising 2825 to 15,258 single-cell images to train and test the model. Findings: With 1% annotations (18–114 cells), SANDI achieved weighted F1-scores ranging from 0.82 to 0.98 across the five datasets, which was comparable to the fully supervised classifier trained on 1828–11,459 annotated cells (−0.002 to −0.053 of averaged weighted F1-score, Wilcoxon rank-sum test, P = 0.31). Leveraging the immune checkpoint markers stained in ovarian cancer slides, SANDI-based cell identification reveals spatial expulsion between PD1-expressing T helper cells and T regulatory cells, suggesting an interplay between PD1 expression and T regulatory cell-mediated immunosuppression. Interpretation: By striking a fine balance between minimal expert guidance and the power of deep learning to learn similarity within abundant data, SANDI presents new opportunities for efficient, large-scale learning for histology multiplex imaging data. Funding: This study was funded by the Royal Marsden/ICR National Institute of Health Research Biomedical Research Centre.

Objective: To determine the association between Intra-articular mineralization (IAM) and knee osteoarthritis (OA) outcomes stratified according to participants’ age. Methods: Participants from the Osteoarthritis Initiative (OAI) with baseline radiographic OA (i.e., Kellgren-Lawrence grade ≥2 with Osteoarthritis Research Society International (OARSI) atlas joint space narrowing (JSN)) in either knee were identified. Both knees and dominant hand baseline radiographs were evaluated for the presence of IAM. Whole-grade OARSI-JSN radiographic progression and increased Western Ontario and McMaster universities osteoarthritis index scores of the knees with baseline radiographic OA (assessed annually) were defined as radiographic and symptomatic progression, respectively. Cox proportional-hazards and longitudinal multilevel regression models investigated radiographic and symptomatic progression, respectively. Results: 2010 participants with baseline radiographic OA in either one or both knees (N ​= ​2976) were identified. 178 participants had baseline IAM (hand radiographs ​= ​46, knee radiographs ​= ​166, both ​= ​34). An adjusted logistic regression model suggests an association between age and IAM (Odds Ratio: 1.06, 95% Confidence Interval (CI): 1.04–1.08). Presence of any IAM was not associated with whole-grade OARSI-JSN (Hazard Ratio (HR): 1.00, 95% CI: 0.73–1.37) or symptomatic progression (Estimated difference: 1.24, p-value: 0.13) in all participants. Using stratification analysis, in younger participants

Personal thermal management is emerging as a promising strategy to provide thermal comfort for the human body while conserving energy. By improving control over the heat dissipating from the human body, personal thermal management can provide effective personal cooling and warming. Here, we propose a facile surface modification approach to tailor the thermal conduction and radiation properties based on commercially available fabrics, to realize better management of the whole heat transport pathway from the human body to the ambient. A bifunctional asymmetric fabric (BAF) offering both a cooling and a warming effect is demonstrated. Due to the advantages of roughness asymmetry and surface modification, the BAF demonstrates an effective cooling effect through enhanced heat conduction and radiation in the cooling mode; in the warming mode, heat dissipation along both routes is reduced for personal warming. As a result, a 4.6 °C skin temperature difference is measured between the cooling and warming BAF modes, indicating that the thermal comfort zone of the human body can be enlarged with one piece of BAF clothing. We expect this work to present new insights for the design of personal thermal management textiles as well as a novel solution for the facile modification of available fabrics for both personal cooling and warming.

Objective: The anti-CD38 antibody Isa in combination with Kd is approved in various countries for patients (pts) with relapsed MM after ≥1 prior therapy, based on primary interim analysis (IA) of the Phase 3 IKEMA study (NCT03275285). Here we report updated efficacy and safety Results from IKEMA. Methodology: This prespecified final analysis (Isa-Kd 179, Kd 123 pts) evaluated updated PFS (primary endpoint), PFS2, CR rate, MRD- rate, and MRD- and CR rate in ITT population, and safety with 2 additional years of follow-up. Isa 10mg/kg was given IV qw for 4 wks and then q2w; Kd 20/56mg/m² biw, 3/4 weeks. Hydrashift Isa IF assay was used to rule out potential Isa interference in CR determination. At cutoff (14Jan2022; median follow-up 44 mo), 49 (27.4%) Isa-Kd, 11 (8.9%) Kd pts were still on treatment. Results: Updated PFS was consistent with primary IA Results, showing significant benefit of Isa-Kd (vs Kd): PFS HR 0.58; PFS2 HR 0.68. Final CR rate (Isa-Kd vs Kd) was 44.1% vs 28.5%, MRD- rate 33.5% vs 15.4%, MRD- and CR rate 26.3% vs 12.2% (Table). Serious TEAEs were reported in 70.1% Isa-Kd vs 59.8% Kd pts. The most common, any-grade non-hematologic TEAEs in Isa-Kd were infusion reactions (45.8%), diarrhea (39.5%), hypertension (37.9%) and upper respiratory tract infection (37.3%). Conclusion: These Results show unprecedented mPFS, CR rate, MRD- and MRD- CR rates in a non-lenalidomide containing regimen with benefit maintained through subsequent therapies and a manageable safety profile. Safety profiles and efficacy Results in both arms were consistent with prior IKEMA findings. Our findings support Isa-Kd as a standard of care treatment for pts with relapsed MM.

Purpose: Bi-parametric magnetic resonance imaging (bpMRI) with diffusion-weighted images has wide utility in diagnosing clinically significant prostate cancer (csPCa). However, bpMRI yields more false-negatives for PI-RADS category 3 lesions than multiparametric (mp)MRI with dynamic-contrast-enhanced (DCE)-MRI. We investigated the utility of synthetic MRI with relaxometry maps for bpMRI-based diagnosis of csPCa. Methods: One hundred and five treatment-naïve patients who underwent mpMRI and synthetic MRI before prostate biopsy for suspected PCa between August 2019 and December 2020 were prospectively included. Three experts and three basic prostate radiologists evaluated the diagnostic performance of conventional bpMRI and synthetic bpMRI for csPCa. PI-RADS version 2.1 category 3 lesions were identified by consensus, and relaxometry measurements (T1-value, T2-value, and proton density [PD]) were performed. The diagnostic performance of relaxometry measurements for PI-RADS category 3 lesions in peripheral zone was compared with that of DCE-MRI. Histopathological evaluation results were used as the reference standard. Statistical analysis was performed using the areas under the receiver operating characteristic curve (AUC) and McNemar test. Results: In 102 patients without significant MRI artefacts, the diagnostic performance of conventional bpMRI was not significantly different from that of synthetic bpMRI for all readers (p = 0.11–0.79). The AUCs of the combination of T1-value, T2-value, and PD (T1 + T2 + PD) for csPCa in peripheral zone for PI-RADS category 3 lesions were 0.85 for expert and 0.86 for basic radiologists, with no significant difference between T1 + T2 + PD and DCE-MRI for both expert and basic radiologists (p = 0.29–0.45). Conclusion: Synthetic MRI with relaxometry maps shows promise for contrast media-free evaluation of csPCa.

While originally intended to transform research and innovation practice, the concept of responsible research and innovation (RRI) has largely remained a theoretical, policy-oriented construct, thereby engendering a perception that RRI indicators are very different from organizational or business indicators. As there is currently limited experience with RRI in businesses, in an attempt to gain more insights into RRI in practice, this paper focuses on an exploratory assessment of key performance indicators (KPIs) in a nanomedicine project. Based on correspondence analysis, we visually demonstrate associations among KPIs of RRI dimensions and of organizational ongoing R&D dimensions implying that these two indicators are not entirely different from each other and may even be potentially aligned. This finding may stimulate the motives of the RRI uptake in practice.

Summary: BTN3A molecules—BTN3A1 in particular—emerged as important mediators of Vγ9Vδ2 T cell activation by phosphoantigens. These metabolites can originate from infections, e.g. with Mycobacterium tuberculosis, or by alterations in cellular metabolism. Despite the growing interest in the BTN3A genes and their high expression in immune cells and various cancers, little is known about their transcriptional regulation. Here we show that these genes are induced by NLRC5, a regulator of MHC class I gene transcription, through an atypical regulatory motif found in their promoters. Accordingly, a robust correlation between NLRC5 and BTN3A gene expression was found in healthy, in M. tuberculosis-infected donors' blood cells, and in primary tumors. Moreover, forcing NLRC5 expression promoted Vγ9Vδ2 T-cell-mediated killing of tumor cells in a BTN3A-dependent manner. Altogether, these findings indicate that NLRC5 regulates the expression of BTN3A genes and hence open opportunities to modulate antimicrobial and anticancer immunity.

Summary: Background: Phone hygiene is increasingly recognized in infection prevention. We aimed to explore the beliefs, attitudes and performance of phone hygiene amongst healthcare workers (HCWs) in the major operation theatre (MOT) complex of a Singapore tertiary acute care hospital. We also monitored the impact of phone hygiene stations, introduced to improve phone hygiene. Methods: We sent two online anonymous surveys to the Departments of Anaesthesia and MOT Nurses one month before and after we set up phone hygiene stations. Four phone hygiene stations displaying visual phone hygiene reminders and Mikrozid® sensitive wipes were set up at MOT entrances. Results: A total of 205 and 91 HCWs responded to the first and second surveys respectively. In the first survey, 11.5% cleaned their phones daily while 9.4% never cleaned their phones. These changed to 16.9% and 3.8% respectively after the introduction of phone hygiene stations. 80.0% in the first survey said they would clean their phones more often if there were a readily accessible disinfection method in the MOT. A majority believed phones are a source of healthcare associated infection. Common reasons for not cleaning phones were ‘lack of available resources’ and ‘I don't think about it.’ Senior doctors were the least compliant to phone hygiene. Conclusion: Phone hygiene is easily overlooked during our busy workday. Besides increasing awareness of phone hygiene, having a readily available disinfection method in the MOT complex is important to improve phone hygiene. We suggest HCWs clean their phones before entering and/or after leaving the MOT daily. Keywords: Mobile phone hygiene, Infection control, Beliefs, Attitudes, Performance, Wipes, Healthcare workers, Major operation theatre

Clinical prediction of advanced hepatic fibrosis (HF) and cirrhosis has long been challenging due to the gold standard, liver biopsy, being an invasive approach with certain limitations. Less invasive blood test tandem with a cutting-edge machine learning algorithm shows promising diagnostic potential.In this study, we constructed and compared machine learning methods with the FIB-4 score in a discovery dataset (n = 490) of hepatitis B virus (HBV) patients. Models were validated in an independent HBV dataset (n = 86). We further employed these models on two independent hepatitis C virus (HCV) datasets (n = 254 and 230) to examine their applicability.In the discovery data, gradient boosting (GB) stably outperformed other methods as well as FIB-4 scores (p < .001) in the prediction of advanced HF and cirrhosis. In the HBV validation dataset, for classification between early and advanced HF, the area under receiver operating characteristic curves (AUROC) of GB model was 0.918, while FIB-4 was 0.841; for classification between non-cirrhosis and cirrhosis, GB showed AUROC of 0.871, while FIB-4 was 0.830. Additionally, GB-based prediction demonstrated good classification capacity on two HCV datasets while higher cutoffs for both GB and FIB-4 scores were required to achieve comparable specificity and sensitivity.Using the same parameters as FIB-4, the GB-based prediction system demonstrated steady improvements relative to FIB-4 in HBV and HCV cohorts with different cutoff values required in different etiological groups. A user-friendly web tool, LiveBoost, makes our prediction models freely accessible for further clinical studies and applications. Keywords: Hepatic fibrosis, FIB-4, Hepatitis B, Hepatitis C, Machine learning, Gradient boosting

Aim: To measure skin thickness (ST) and skin + subcutaneous layer thickness (SCT) by ultrasound and estimate the risk of intramuscular injection (IM) with different needle lengths across injection sites according to age group. Method: Children recruited between 1 and 18 years with type 1 and 2 diabetes on insulin injections and divided into three age groups: 1–6 years, 7–12 years and 13–18 years. A portable ultrasound was used to measure ST and SCT at four injection sites on the abdomen, arm, thigh and buttock. Results: Total 153 children enrolled for the study. The mean (SD) measurement of ST & SCT at four sites on abdomen, arm, thigh & buttocks were as follows; 4.33 mm (±2.22), 5.55 mm (±2.26), 5.83 mm (±3.12), 6.48 mm (±3.47) in 1–6 years old; 7.11 mm (±3.68), 7.79 mm (±4.54), 7.17 mm (±3.62), 8.51 mm (±3.65) in 7–12 years old; 8.94 mm (±4.50), 8.42 mm (±5.00), 8.61 mm (±4.76), 9.76 mm (±4.38) in 13–18 years old. Young children, 1–6 years have the highest risk of IM injection with all needle lengths, i.e. 4, 5, 6, 8 & 12.7 mm, while older children 7–12 & 13–18 years have a lower risk with shorter needles (4, 5 and 6 mm) as compared to longer needles (8 and 12.7 mm). Conclusions: Children with diabetes on insulin therapy should be advised on the appropriate needle length accordingly to their age and BMI.

Aquaporin-4 (AQP4) is a water conducting membrane integral protein channel which is widely expressed in the astrocyte system of the brain. During the development of the AQP4 positron emission tomography (PET) imaging agent [11C]TGN-020 (N-(1,3,4-thiadiazol-2-yl)pyridine-3-[11C]-carboxamide), significant radioligand uptake was observed in the skull, where there was no known distribution of any aquaporin family proteins. Herein we confirmed via a newly developed method for bone-tissue immunohistology, a hitherto unrecognized distribution of AQP4, and not AQP1, in the skull. Other bony structures, by contrast, showed virtually no uptake of [11C]TGN-020, and likewise, do not express either AQP4 or AQP1. Immunohistological analysis demonstrated that the AQP4 expression in the skull is restricted to the diploë. Consequently, we suspect AQP4 plays a pivotal role in the formation and maintenance of yellow marrow and the diploë. However, elucidating the exact nature of that role will require further studies.

Background: Multiple myeloma (MM) is associated with high healthcare resource utilisation and increasing hospitalisation rates. The aim of this study was to characterise the hospital use by patients with MM in the English National Health Service (NHS). Methods: Routinely-collected aggregate data about all NHS-funded hospital admissions of patients with MM were analysed. Data were obtained from the English Hospital Episodes Statistics on admissions between 1 April 2014 and 31 March 2018. Results: A total of 754,345 admissions were reported over four years, equivalent to a mean of 188,586 admissions per year. Of the 41,845 patients admitted during this period, 42% were women and 58% men. From the total admissions, 90% were elective and 10% unplanned. Mean annual estimated costs over the period were £46 million for elective and £56 million for unplanned admissions. The number of elective admissions increased by 4.5% with costs increasing 1.5% per year; for unplanned admissions, these figures were 4.1% and 9.0%, respectively. Conclusions: MM is associated with a significant number of hospital admissions and NHS costs. The majority of the hospital admissions are elective, but the highest burden in terms of costs relates to unplanned admissions, with numbers increasing over time. Keywords: Multiple myeloma, Unplanned admissions, Elective admissions, Costs

Nutrients and temperature are the major elements in maintaining stable endosymbiotic relationships. The mechanisms and response of cultured Symbiodinium cells in the absence of nitrogen, and at various temperatures are still unclear. The present study investigated the influence of different temperatures and nitrogen-deprivation on free-living Symbiodinium cultures. The physiological responses of free-living Symbiodinium cells cultured at different temperatures during nitrogen deprivation under a 12:12 h light:dark were measured. Symbiodinium cell growth was significantly lower in response to lower temperatures. Transmission electron micrographs (TEMs) revealed the formation of lipid droplets induced by nitrogen deprivation under different temperatures. The results of this study will increase our understanding of adaptive responses occurring in Symbiodinium under environmental stress.

In this study, we present the identification and characterization of hamster and guinea pig nicotinic acid receptors. The hamster receptor shares ∼80–90% identity with the nucleotide and amino acid sequences of human, mouse, and rat receptors. The guinea pig receptor shares 76–80% identity with the nucleotide and amino acid sequences of these other species. [3H]nicotinic acid binding affinity at guinea pig and hamster receptors is similar to that in human (dissociation constant = 121 nM for guinea pig, 72 nM for hamster, and 74 nM for human), as are potencies of nicotinic acid analogs in competition binding studies. Inhibition of forskolin-stimulated cAMP production by nicotinic acid and related analogs is also similar to the activity in the human receptor. Analysis of mRNA tissue distribution for the hamster and guinea pig nicotinic acid receptors shows expression across a number of tissues, with higher expression in adipose, lung, skeletal muscle, spleen, testis, and ovary.

Peroxisome proliferator-activated receptor-δ (PPAR-δ) is a ligand-activated transcription factor. In addition to its canonical role in lipid, glucose metabolism, PPAR-δ controls cell proliferation, death, differentiation in several tissues. Here we have examined the expression of PPAR-δ in ovarian tumors, the cellular, molecular consequences of its activation in ovarian cancer cells. PPAR-δ was expressed in a large number of epithelial ovarian tumors, cell lines. The PPAR-δ lig, ciglitazone inhibited the growth, clonogenic survival of ovarian cancer cells, inducing cell cycle arrest, cell death. Growth inhibition by ciglitazone was reversed by the PPAR-δ antagonist GW9662, indicating the involvement of PPAR-δ- dependent mechanisms. Microarray-based gene profiling revealed complex changes in the transcriptional program of ovarian cancer cells on treatment with ciglitazone, identified multiple pathways that may contribute to PPAR-δ ligands' antitumor activity. Genes upregulated by ciglitazone were predominantly associated with metabolic, differentiation, tumorsuppressor pathways, whereas downregulated genes were involved in cell proliferation, cell cycle, cell organization, steroid biosynthesis. Collectively, our data indicate that PPAR-δ activation by selective agonists is a valid strategy for ovarian cancer therapy, prevention, should be tested alone, in combination with other anticancer drugs.

When restrained in a quasi-fetal position, infant rats (2--3 weeks old) remain for an extended period in a sleep-like state as judged by polygraphic criteria. Moreover, they become very difficult to arouse by sensory stimuli, and show a level of spontaneous motility considerably higher than is normally found at this age during sleep. Phasic generalized body movements, which are often quite stereotyped, occur in trains at regular intervals, against a low background level of neck muscle tonus. The amplitude of the cortical EEG, especially in the delta band, is negatively correlated with the frequency of spontaneous motor burst activity. It is suggested that these REM-like "rapid body movements" in immature mammals may well represent a transitional stage between fetal behavior patterns and sleep motility in the adult organism.