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PurposeEntinostat is an oral isoform selective histone deacetylase inhibitor that targets resistance to hormonal therapies in estrogen receptor-positive (ER+) breast cancer. This randomized, placebo-controlled, phase II study evaluated entinostat combined with the aromatase inhibitor exemestane versus exemestane alone.Patients and methodsPostmenopausal women with ER+ advanced breast cancer progressing on a nonsteroidal aromatase inhibitor were randomly assigned to exemestane 25 mg daily plus entinostat 5 mg once per week (EE) or exemestane plus placebo (EP). The primary end point was progression-free survival (PFS). Blood was collected in a subset of patients for evaluation of protein lysine acetylation as a biomarker of entinostat activity.ResultsOne hundred thirty patients were randomly assigned (EE group, n = 64; EP group, n = 66). Based on intent-to-treat analysis, treatment with EE improved median PFS to 4.3 months versus 2.3 months with EP (hazard ratio [HR], 0.73; 95% CI, 0.50 to 1.07; one-sided P = .055; two-sided P = .11 [predefined significance level of .10, one-sided]). Median overall survival was an exploratory end point and improved to 28.1 months with EE versus 19.8 months with EP (HR, 0.59; 95% CI, 0.36 to 0.97; P = .036). Fatigue and neutropenia were the most frequent grade 3/4 toxicities. Treatment discontinuation because of adverse events was higher in the EE group versus the EP group (11% v 2%). Protein lysine hyperacetylation in the EE biomarker subset was associated with prolonged PFS.ConclusionEntinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ER+ advanced breast cancer in this signal-finding phase II study. Acetylation changes may provide an opportunity to maximize clinical benefit with entinostat. Plans for a confirmatory study are underway.

A structure and growth pattern of Squalius cephalus (Linnaeus, 1758) in Tuji tributary of Talar River, Mazandaran Province, was studied during the period from August 2008 till August 2009. In total, 298 fish were caught by electrofishing and fixed in 10% formalin. The weight and length of fish were measured and the age was determinated by scallometric method. The age data showed that fishes were between 0+ to 4+ age groups. Pauli`s applied growth pattern showed a positive alometric for male and female and total fish and a negative isometric for unmature fishes. The average instantaneous growth rate of European Chub showed that the age groups 2+ and 3+ with 1.1 had the fastest growth compare to 3+ and 4+ age groups with 0.89. Condition factor of specimens showed that the highest one with 1.58 (r2 = 0.983) belong to females and the lowest with 1.17 (r2 = 0.901) belong to unmature fishes. The total sex ratio (123 males to 115 females) showed no significant differences between them.

BACKGROUND AND OBJECTIVE: Identification of cancer risk factors in the community and prevention planning in high-risk groups can be helpful in cancer prevention program. Hence, the aim of this study was to investigate the relationship between reproductive factors and breast cancer in the Tabari population-based cohort study in a case-control design. METHODS: This case-control study was performed on the enrolment phase of the Tabari population-based cohort. Patients with breast cancer were considered as case group (51) and non-cancerous individuals (204) as a control group. The two groups were matched based on age category and oral contraceptive pill (OCP) intake. The studied variables included breast cancer history, demographic and reproductive factors. FINDINGS: Mean age of first pregnancy (22.76±4.99 vs. 20.8±4.16, p=0.005), mean age at first birth (23.57±4.94 vs. 21.66±4.07, p=0.006) and age of marriage (22.24±5.75 vs. 19.54±4.92, p=0.001) in the case group were significantly higher than the control group and the number of pregnancies (3.76±2.22 vs. 4.67±2.76, p=0.032) and number of children (3.27±1.97 vs. 4.16±2.44, p=0.019) in the case group was significantly less than the control group. According to multivariate analysis, the odds of incidence of breast cancer in people with first pregnancy over 22 years was 2.76 times more than (p= 0.027) those with first pregnancy age below 22 years. CONCLUSION: "Age at first full-term pregnancy" is one of the major risk factors for breast cancer in the area. [ABSTRACT FROM AUTHOR]

Introduction: Hypothyroidism is a known consequence of external-beam radiotherapy to the neck encompassing a part or whole of the thyroid gland. In this non-randomized prospective study, we have tried to evaluate the response of the thyroid gland to radiation by assessing thyroid function before irradiation and at regular intervals after irradiation. Aims and Objectives: The aim of this study were to assess in the cancer patients, who were exposed to the therapeutic external beam radiation, where radiation portals include a part or whole of the thyroid gland: the incidence of primary hypothyroidism, the time required to become hypothyroid, any relation between the total dose for the development of hypothyroidism, and whether there are any patient or treatment-related factors that are predictive for the development of hypothyroidism, including the use of concurrent chemotherapy. Materials and Methods: This non-randomized, prospective study was conducted for a period of 2 years in which thyroid function was assessed in 59 patients (cases) of head and neck cancer, breast cancer, lymphoma patients and other malignancies, who had received radiotherapy to the neck region. 59 euthyroid healthy patients (controls) were also taken, who had not received the neck irradiation. These patients/controls were assessed periodically for 2 years. Results: The incidence of hypothyroidism after external beam radiation therapy (EBRT) to neck where radiation portals include part or whole of the thyroid gland was 16.94%, seven cases had subclinical hypothyroidism (11.86%) and three cases had clinical hypothyroidism (5.08%). Mean time for development of hypothyroidism was 4.5 months. There was no effect of age, gender, primary tumor site, radiation dose and chemotherapy, whether neoadjuvant or concurrent with the development of hypothyroidism. Conclusion: In summary, we found that thyroid dysfunction is a prevalent, yet easily treatable source of morbidity in patients undergoing radiation therapy to neck where radiation portals include a part or whole of the thyroid gland. [ABSTRACT FROM AUTHOR]

Objective: This article provides readers with a foundational understanding of epilepsy, including epilepsy classification, and presents a strategic approach to the diagnosis of seizures and epilepsy., Latest Developments: Epilepsy classification systems have evolved over the years, with improved categorization of seizure types and adoption of more widely accepted and comprehensible terminologies. The International League Against Epilepsy (ILAE) Classification of the Epilepsies (2017) introduces a three-tiered framework. The levels focus on the determination of seizure type, epilepsy type, and identification of epilepsy syndrome, when applicable. The 2017 ILAE classification emphasizes the evaluation of the underlying etiology of epilepsy and the identification of associated comorbidities at all stages of classification. Epilepsy syndromes often have age-dependent symptoms., Essential Points: A systematic approach to the classification of seizures and epilepsy is essential for the selection of appropriate diagnostic tests and treatment strategies. An accurate classification not only facilitates clinical assessment but has important implications in the determination of prognosis., (Copyright © 2025 American Academy of Neurology.)

Introduction: Hyperkalemia is frequently encountered and associated with cardio-vascular mortality in chronic hemodialysis (HD) patients. While online hemodiafiltration (OL-HDF) is thought to offer clinical benefit over high-flux HD, the impact of convective clearance on intra-dialytic potassium removal is unknown., Methods: Chronic dialysis patients undergoing outpatient HD or OL-HDF at a single center attached to a university hospital were recruited in a prospective observational study. Spent dialysate along with clinical and biological variables were collected during a single mid-week session., Results: We included 141 patients, with 21 treated with HD and 120 with OL-HDF. Mean age was 65.7 ± 15.6 years with 87 (61.7%) men. Mean intra-dialytic potassium removal was 69.9 ± 34.2 mmol. Patients on OL-HDF and HD have similar intra-dialytic potassium removal, with mean values of 69.1 ± 34.2 and 74.3 ± 35.0, respectively. In multivariate analysis, factors associated with intra-dialytic potassium removal were (decreasing order of effect size): dialysate potassium (β -15.5, p < 0.001), pre-HD serum potassium (β 9.1, p < 0.001), and session time (β 7.8, p = 0.003). In OL-HDF patients, substitution flow was not associated with potassium removal., Conclusion: In chronic dialysis patients, convective therapy provided by OL-HDF does not affect potassium removal when compared with high-flux HD. Moreover, the importance of convective volume is not associated with potassium clearance in OL-HDF. Overall, session length and serum-to-dialysate potassium gradient are the main determinants of potassium clearance regardless of dialysis modality. Those results should inform clinicians on the optimal therapy in chronic dialysis patients in the era of OL-HDF., (© 2024 The Author(s). Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Polyhydroxyalkanoates (PHAs) are promising polymer in the battle against plastic pollution. Here, Rhodococcus qingshengii LS18 bacterial strain recovered from abattoir soil was identified as significant PHA producer (2.16 g/L PHA). Amongst five animal wastes tested, chicken feathers (2.2 g/L) were found to be best for PHA production from R. qingshengii LS18. Finest conditions for PHA production after statistical optimization were found at 120 h with 40 g/L chicken feathers and 1 g/L urea at 80 rpm which showed 2.6 times increment in PHA production as compared to One-factor-at-a-time optimization (OFAT). The extracted PHA was analysed using NMR, FTIR, XRD and GCMS. The melting temperature (T m ) of microbial PHA was recorded at 176.63 °C as per DSC analysis and this polymer suffered complete disintegration at ~ 300 °C as per the TGA profile which is better than the standard PHA (~ 283.14 ± 10 °C). Blending of microbial PHA was done to overcome the brittleness with sole extracted PHA and for better degradation capability. Best PHA blend obtained with gelatin and Egg shell powder (ESP) in ratio 2:1:1 where 94% Elongation at break, 62% Elongation at max load and 9.81 MPa Tensile strength was found. Here, biodegradation rate of PHA blend in unaltered garden soil (at 30-40 °C, humidity ~ 30%, pH 7.4) was recorded to be 94% on 60th day of soil burial experiment. The study concludes that R. qingshengii LS18 is a promising PHA producer having the ability to utilize chicken feathers in optimised conditions and can be used for packaging applications in the form of PHA blends., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Delivering optimal care to patients with seizures and epilepsy requires all EEGs to be interpreted accurately and reliably. This study investigated neurology professionals' opinions on the ideal standards for EEG in clinical care., Methods: We developed an anonymous e-survey targeting practicing and trainee neurologists focused on participants' demographics, clinical practice characteristics, and views on optimal EEG standards of care-including whether an EEG certification test is needed and whether postresidency/fellowship training in EEG/epilepsy is necessary for neurologists who interpret outpatient/routine EEGs in practice. The survey was hosted by the Neurology Clinical Practice-Practice Current, and it was distributed online through the American Academy of Neurology, American Epilepsy Society, American Clinical Neurophysiology Society, and International League Against Epilepsy, and through social media., Results: Two hundred eighty-three responses were included: 119 from EEG/epilepsy-trained neurologists, 83 from non-EEG/epilepsy-trained neurologists, 75 from trainees, and 6 from advanced care providers. Most participants (78%) agreed that "an objective certification test of ability to interpret EEGs is needed for all those who interpret EEGs in clinical practice." Most participants (71%) believed that outpatient/routine EEGs may be read only by neurologists with EEG/epilepsy training; this opinion was more prevalent among EEG/epilepsy-trained (83%) versus non-EEG/epilepsy-trained neurologists (55%)., Conclusions: Our neurology community should discuss the need to develop and implement a certification test of ability for all neurologists who wish to interpret EEGs in clinical practice. In addition, it is imperative to improve in-residency EEG education to ensure that neurology graduates achieve EEG competence before entering the workforce., (Copyright © 2025 by the American Clinical Neurophysiology Society.)

A toddler presented to audiovestibular medicine with mild bilateral, sensorineural hearing loss identified via the Newborn Hearing Screening Programme. This report focuses on the early clinical assessment and aetiological investigation which prompted testing for metabolic disease and highlights the parents' perspective. Early investigation led to a relatively early diagnosis of mucopolysaccharidosis (MPS) type IIIA: Sanfilippo disease which enabled the family to access a novel treatment option which otherwise would not have been possible.Infants with early signs and symptoms of MPS may present to a range of healthcare professionals. The detection of hearing loss via the newborn hearing screen presents an opportunity for healthcare professionals to initiate early investigation for a possible underlying metabolic disease before end-organ damage progresses. This is vital in allowing affected families to engage with clinical trials and genetic counselling., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

The study aimed to investigate the effect of thermosonication (TS; 37 KHz, 300 W; 30, 40, 50, and 60 °C for 10 min) and NaCl (12 % w/v) on the inactivation of Staphylococcus aureus and Shigella flexneri in lettuce, as well as to examine the kinetics of inactivation and the thermodynamic behaviors of the process. Computational Fluid Dynamics (CFD) simulations were employed to analyze the acoustic pressure field, velocity contours, and streamlines. The results showed that NaCl addition had the least impact on inactivation compared to TS and combined NaCl + TS. Increasing the temperature led to higher inactivation of both bacteria, with a more significant effect at 60 °C. Thermosonication treatment had a more consistent effect on inactivation compared to the addition of NaCl. When exposed to thermosonication, the population of S. aureus and S. flexneri could be reduced by 5.1 to 6.9 log CFU/g and 5.5 to 7.4 log CFU/g, respectively, at temperature levels of 30 and 60 °C. Additionally, no significant relationship between entropy reduction and type of microorganisms was observed. The samples that were treated only with NaCl had higher energy absorption than the other samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: The interferon regulatory factor 7 (IRF7), a member of the IRF family of transcription factors, plays a major role in the regulation of numerous aspects of an immune response and has increasingly been surveyed to determine the aetiology and pathogenesis of systemic sclerosis (SSc). Objective: This study aimed to investigate the transcriptional levels of IRF7 mRNA in peripheral blood mononuclear cells (PBMCs) and the impact of promoter methylation on IRF7 mRNA expression in SSc patients compared to healthy controls., Methods: PBMCs were obtained from confirmed 40 naïve SSc cases and 20 healthy controls for IRF-7 expression and methylation analysis. mRNA expression was performed using the quantitative real-time polymerase chain reaction (SYBR green method) concerning the housekeeping gene. A promoter methylation profile study was carried out by bisulfite treatment of DNA, followed by methylation-specific polymerase chain reaction (MS-PCR) in SSc cases against controls., Results: The relative expression analysis revealed that the selected IRF7 gene was upregulated in the patient group compared to healthy controls (p=0.003). In addition, mRNA expression of IRF7 was significantly increased in the limited cutaneous group compared to the diffuse cutaneous group. Moreover, SSc cases had hypomethylated IRF7 promoters compared to controls, and the significant impact of IRF7 promoter methylation on mRNA expression was observed (p=0.001)., Conclusion: IRF7 overexpression in PBMCs from SSc patients may be caused by IRF7 promoter demethylation, and this aberrant expression of IRF7 in SSc might provide a link between the prominent IFN signature and the development of SSc., Competing Interests: The authors declare no conflict of interest., (© The Author(s).)

Objective: Stereotactic neuromodulation, such as deep brain stimulation (DBS) and responsive neurostimulation (RNS), have emerged as some of the more promising means for managing drug-resistant epilepsy. This study serves as a comprehensive analysis of DBS of the anterior nucleus of the thalamus (ANT), centromedian thalamic nucleus (CMT), and hippocampus and RNS for seizure reduction in adult intractable epilepsy., Methods: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic review was conducted of PubMed, Cochrane Library, and Embase databases from January 2000 to January 2024 to objectively assess the effectiveness of the various neuromodulation modalities on seizure reduction. Different software such as EndNote and Rayyan was utilized to organize the 1996 total reviewed studies and to run a blinded multi-phase review process., Results: A total of 25 studies were included for review with 21 studies and 166 patients suitable for the meta-analysis. DBS ANT, DBS hippocampus, and RNS were all found to have significant individual seizure reductions of 54.0%, 70.0%, and 63.5%. DBS CMT was excluded since only 1 study met inclusion criteria and was, therefore, not suitable for meta-analysis. Furthermore, the 3 analyzed procedures were found to be not significant when compared to one another. Focal versus general epilepsy in DBS ANT also had no significant difference. DBS hippocampus had a significantly higher reduction rate in patients with mesial temporal sclerosis compared to patients with normal imaging findings., Conclusion: These results provide a vast amount of supporting data for these neurostimulation procedures while also indicating no significant difference between operations. Therefore, in this target population, operative decisions can be made based on surgeon preference and patient circumstance without affecting seizure reduction outcomes., (Copyright © 2024. Published by Elsevier Inc.)

Autoimmune diseases pose a significant challenge due to their complex pathogenesis and rising prevalence. Traditional therapies are often limited by systemic side effects, immunosuppression, and lack of long-term efficacy. Mesenchymal stem cells (MSCs) have demonstrated immunomodulatory properties, primarily through the secretion of extracellular vesicles (EVs), which are now recognized as potent mediators of immune regulation. MSC-derived EVs carry bioactive molecules such as microRNAs, proteins, and lipids that influence key immune pathways, making them a promising therapeutic avenue for autoimmune diseases. This review critically examines the immunomodulatory mechanisms of MSC-derived EVs, focusing on their role in regulating T cells, B cells, and macrophages, which are central to autoimmune pathology. We explore recent preclinical and clinical studies that highlight the ability of MSC-derived EVs to reduce inflammation, promote immune tolerance, and restore tissue homeostasis in autoimmune settings. Furthermore, we discuss the advantages of EV-based therapy over MSC-based therapies, including improved safety profiles, lower immunogenicity, and scalability for clinical application. By evaluating the current landscape of MSC-derived EV research, we identify key gaps and propose innovative strategies to optimize EVbased therapies for autoimmune diseases. These strategies include engineering EVs to enhance their specificity and therapeutic efficacy, as well as integrating them with biomaterials for targeted delivery. Our review aims to provide a forward-looking perspective on the potential of MSC-derived EVs as a novel therapeutic approach, moving beyond traditional cell-based therapies to offer more precise and personalized treatment options for autoimmune diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: As a master immune system regulator, transforming growth factor β1 (TGF-β1) is closely linked to the complicated pathophysiology and development of systemic sclerosis (SSc), a multisystem fibrotic disease., Objective: We aim to evaluate the transcriptional levels of TGF-β1 mRNA in PBMCs, assess the TGF-β1 serum levels of SSc patients, and compare them with those of healthy subjects., Methods: PBMCs were isolated from whole blood of 50 SSc patients and in 30 healthy controls. After total RNA was extracted from isolated PBMCs, complementary DNA (cDNA) synthesis was performed. Afterward, the expression of TGF-β1 mRNA was assessed using quantitative real-time PCR using the SYBR Green, GAPDH, and TGF-β1 specific primers. The serum levels of TGF-β1 were determined using a commercially available ELISA kit., Results: There was a significant upregulation of TGF-β1 relative expression (p < 0.0001), when SSc patients were compared to the control group. The diffuse subgroup was more common in patients with elevated TGF-β1 mRNA expression (p < 0.0001). However, an insignificant difference was observed between the disease subsets of SSc. Serum TGF- β1 levels were upregulated in SSc patients (78.35 ± 23.16) compared to healthy subjects (61.06 ± 15.90), and were considerably higher in SSc patients with ILD (p < 0.01) and positive anti-topo-Isomerase antibody (p < 0.0001)., Conclusion: In patients with SSc, elevated levels of TGF-β1 in serum and their correlation with clinical symptoms imply that this cytokine may serve as a marker for fibrotic and vascular involvement in SSc., Competing Interests: Declarations. Ethical approval: The Institutional Ethics Committee (IEC-SKIMS) approved the study vide protocol number #RP77/2019. Consent to participate: After giving their informed consent and having the right to withdraw at any moment, participants willingly decided to participate in this study. Consent for publication: The patients who participated in this study gave written informed consent for participation and publication of this study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Imlunestrant is a next-generation oral selective estrogen receptor (ER) degrader designed to deliver continuous ER target inhibition, including in ESR1- mutant breast cancer. This phase Ia/b trial determined the recommended phase II dose (RP2D), safety, pharmacokinetics, and efficacy of imlunestrant, as monotherapy and in combination with targeted therapy, in ER-positive (ER+) advanced breast cancer (ABC) and endometrial endometrioid cancer. The ER+/human epidermal growth factor receptor 2-negative (HER2-) ABC experience is reported here., Methods: An i3+3 dose-escalation design was used, followed by dose expansions of imlunestrant as monotherapy or in combination with abemaciclib with or without aromatase inhibitor (AI), everolimus, or alpelisib. Imlunestrant was administered orally once daily and with the combination partner per label., Results: Overall, 262 patients with ER+/HER2- ABC were treated (phase Ia, n = 74; phase Ib, n = 188). Among patients who received imlunestrant monotherapy (n = 114), no dose-limiting toxicities or discontinuations occurred. At the RP2D (400 mg once daily), patients (n = 51) reported grade 1-2 nausea (39.2%), fatigue (39.2%), and diarrhea (29.4%). Patients at RP2D had received previous cyclin-dependent kinase 4/6 inhibitor (CDK4/6i; 92.2%), fulvestrant (41.2%), and chemotherapy (29.4%) for ABC and achieved a median progression-free survival (mPFS) of 7.2 months (95% CI, 3.7 to 8.3). Among patients who received imlunestrant + abemaciclib (n = 42) and imlunestrant + abemaciclib + AI (n = 43), most (69.4%) were treatment-naïve for ABC; all were CDK4/6i-naïve. Patients treated with imlunestrant + everolimus (n = 42)/alpelisib (n = 21) had received previous CDK4/6i (100%), fulvestrant (34.9%), and chemotherapy (17.5%) for ABC. No new safety signals or interactions with partnered drugs were observed. The mPFS was 19.2 months (95% CI, 13.8 to not available) for imlunestrant + abemaciclib and was not reached for imlunestrant + abemaciclib + AI. The mPFS with imlunestrant + everolimus/alpelisib was 15.9 months (95% CI, 11.3 to 19.1)/9.2 months (95% CI, 3.7 to 11.1). Antitumor activity was evident regardless of ESR1 mutation status., Conclusion: Imlunestrant, as monotherapy or in combination with targeted therapy, had a manageable safety profile with evidence of preliminary antitumor activity in ER+/HER2- ABC.

The latest strain of Oreochromis niloticus is an altered ecological adaptation for sustainable aquaculture and is necessary to sustain stocking density and reduce physiological stress of the new strain. The present study aimed to determine the optimum stocking density, biological performance, and economic efficiency of the Nile tilapia. The 14,000 healthy seeds and uniform weight (40 ± 2.4 g) sex-reversed Oreochromis niloticus were stocked in four cages, which are cage (1) 20 fish/m 3 , cage (2) 30 fish/m 3 , cage (3) 40 fish/m 3 , and cage (4) 50 fish/m 3 . The fish were fed 30% dietary protein and feeding frequency three times per day and the feeding rate adjusted according to the fish body weight. Results showed a significantly higher growth, weight gain, and specific growth rate in Nile tilapia stocking density on cage (1), 20 fish/m 3 and cage (2), 30 fish/m 3 compared to cage (3), 40 fish/m 3 and cage (4), 50 fish/m 3 ( p < .05). The survival and growth rate showed an inverse relationship with stocking density. The feed conversion ratio (FCR) is the lowest in cage (1) and cage (2), which is significantly different from those of other cages ( p < .05). The profit index (%) was significantly higher at low density. There was no significant variation in the HSI, VSI and CF. The digestive enzymes such as lipase and amylase were secreted highly in the cages (3) and (4) but high protease was secreted in cage (1). The lipid, ash, and protein of the whole fish were reduced to a lower density, but the moisture levels in the fish bodies raised significantly ( p < .05) with increasing stocking density. The phenomenal regression indicates that 25-35 fish/m 3 are optimum stocking density for Nile tilapia in the cage culture system. The current study has made significant step toward optimizing the stocking density of a new strain and developing cage culture in Pakistan., Competing Interests: All authors declare no conflicts of interest., (© 2024 The Author(s). Food Science & Nutrition published by Wiley Periodicals LLC.)

Targeting of the estrogen receptor (ER) by anti-estrogens is the standard-of-care for patients with ER+ HER2- advanced/metastatic breast cancer. While anti-estrogens that degrade ERα (fulvestrant) or block estrogen production (aromatase inhibitors) have improved patient outcomes, clinically important challenges remain related to drug administration, limited bioavailability, lack of brain exposure, and acquired resistance due to ESR1 mutations. These limitations indicate a need for more robust ER-targeted therapies. Here, we discovered and characterized imlunestrant, a next-generation potent, brain-penetrant oral selective estrogen receptor degrader (SERD). Imlunestrant degraded ERα and decreased ERα-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wildtype and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status. In an ER+ breast cancer intracranial tumor model, imlunestrant prolonged survival compared to vehicle or alternative SERD therapies. Together, these finding support the potential of imlunestrant to degrade ERα and suppress the growth of ESR1 wildtype and mutant breast cancer, including brain metastatic tumors.

Purpose: Imlunestrant is an oral selective estrogen receptor degrader with favorable safety and preliminary efficacy in patients with advanced breast cancer. Pharmacodynamic (PD) biomarker data can optimize drug dosing; in this study, we present PD data from the EMBER-2 study., Patients and Methods: Postmenopausal women with untreated, operable estrogen receptor (ER)-positive, HER2-negative early breast cancer were randomized to 400 versus 800 mg of imlunestrant daily for ∼2 weeks before surgery. A single arm study tested a daily dose of 200 mg. PD biomarker changes (ER, progesterone receptor, Ki-67 by IHC, and mRNA expression of ER-related genes) were evaluated in paired tumor samples (pre-/posttreatment). Safety and pharmacokinetics were also assessed., Results: Among evaluable paired samples (n = 75), PD profiles demonstrated consistent ER targeting between 400- and 800-mg doses, with less toxicity at the 400-mg dose. Although inducing the lowest rate of complete cell-cycle arrest, PD and pharmacokinetic results were similar for the 200-mg dose., Conclusions: EMBER-2 combined with existing phase I data has identified 400 mg as the optimal imlunestrant dose., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objective: Imlunestrant is a next-generation oral selective estrogen receptor degrader designed to deliver continuous estrogen receptor (ER) target inhibition. EMBER is a phase 1a/b trial of imlunestrant, as monotherapy and combined with targeted therapy, in patients with ER+ advanced breast cancer or endometrioid endometrial cancer (EEC). This report focuses on patients with ER+ EEC., Methods: EMBER used an i3 + 3 dose-escalation design to determine the recommended phase 2 dose (RP2D) followed by dose-expansion cohorts (1:1 randomization): imlunestrant monotherapy and imlunestrant plus abemaciclib (150 mg twice daily). Eligible patients had measurable disease and progression or recurrence after platinum-containing chemotherapy. Prior fulvestrant or aromatase inhibitor was not allowed. Secondary endpoints included safety, pharmacokinetics and antitumor activity., Results: In total, 72 patients with a median of 2 prior anticancer therapies were treated. Among the 39 patients who received imlunestrant (400 mg [RP2D], n = 33; 800 mg, n = 6), the most common treatment-emergent adverse events (TEAEs) were grade 1-2 nausea (35.9 %), diarrhea (25.6 %), urinary tract infection (25.6 %), and abdominal pain (20.5 %). Overall response rate (ORR) was 10.3 %, clinical benefit rate (CBR) was 33.3 %, and median progression-free survival (mPFS) was 3.8 months (95 % CI, 1.8-6.7). Among the 33 patients who received imlunestrant (400 mg [RP2D], n = 29; 800 mg, n = 4) plus abemaciclib, the most common TEAEs were diarrhea (87.9 %), nausea (66.7 %), fatigue (48.5 %), and anemia (45.5 %). ORR was 18.2 %, CBR was 42.4 %, and mPFS was 6.8 months (95 % CI, 2.1-12)., Conclusion: Imlunestrant, as monotherapy and combined with abemaciclib, has a manageable safety profile with preliminary evidence of antitumor activity in patients with ER+ EEC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kan Yonemori: Institutional research support:MSD, Daiichi-Sankyo, Merck Biopharma, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle genetics, Eisai, Eli Lilly and company, Genmab, Boeringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, Haihe. Honoraria: Pfizer, Eisai, AstraZeneca, Eli Lilly and Company, Takeda, Chugai, Fuji Film Pharma, PDR pharma, MSD, Boeringer Ingelheim, Ono, Daiichi-Sankyo, Bayer, Jansen, Asteras, Bristol Myers Squibb, Novartis, Sanofi, Merk Biopharma. Advisory board: Eisai, Astra Zeneca, Sanofi, Genmab, Gliad, OncXerna, Takeda, Novartis, MSD, Henlius. Other: Principal investigator (to institution): MSD, Daiichi-Sankyo, Genmab, Seagen, AstraZeneca, Taiho, Merk Biopharma Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle genetics, Eisai, Eli Lilly and company, Genmab, Boeringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, Haihe. Valentina Boni: Institutional research support: Abbvie; ACEO; Adaptaimmune; Amcure; AMGEN; Amunix, AstraZeneca; Bycicle; BMS CytomX; GSK; Genentech/Roche; Genmab; Incyte; Ipsen; Janssen; Kura; Lilly; Loxo Therapeutics; Nektar; Macrogenics; Menarini; Merck; Merus; Nanobiotix; Novartis; Pfizer; PharmaMar; Principia; Puma; Ryvu; Ribbon; Sanofi; Taiho; Tesaro; BeiGene; Transgene; Takeda; Incyte; Innovio; MSD; PsiOxus; Seattle Genetics; Mersana; Daiichi; Nektar; Astellas; ORCA; Boston Therapeutics; Dynavax; DebioPharm; Boehringer Ingelheim; Regeneron; Rigontec; Millennium; Seagen; Synthon; Spectrum; Urogen; Zenith. Consulting fees: Puma Biotechnology; Ideaya Biosciences; Loxo Therapeutics, CytomX Therapeutics; Guidepoint; Oncoart, Lilly; Janssen; EMD Serono; IDMC Nanobiotix NANORAY-312/Novartis; Steering Committee CytomX Therapeutics. Honoraria (speaking): Eli Lilly and Company; MSD; SOLTI; TACTICS; Getthi; Gedefo. Attending meeting and/or travel: Bayer (ESMO GI). Stock/Ownership: 1TRIALSP. Tarek M. Meniawy: Research funding: Bristol Myers Squibb, AstraZeneca, Merck Serono, Roche, BeiGene, MSD, Regeneron, Incyte, GSK. Advisory board: Novartis, GSK, MSD, Sanofi, Eisai, BMS. Attending meeting and/or travel: Bristol Myers Squibb. Peter A. Kaufman: Consulting fees: Eli Lilly and Company. Honoraria: Eli Lilly and Company. Attending meeting and/or travel: Eli Lilly and Company. Debra L. Richardson: Advisory board: Mersana, AstraZeneca, GSK, Immunogen, Eisai, ProfoundBio, Daiichi-Sankyo. Koji Matsumoto: Research funding: Daichi-Sankyo, MSD, Eli Lilly and Company, Gilead Sciences, Eisai. Honoraria: MSD, Kyowa Kirin, Daichi-Sankyo, Eli Lilly and Company, Chugai. Karthik V. Giridhar: Research funding: Guardant Health; Advisory board: AstraZeneca, Eli Lilly and Company, Novartis, Neogenomics, TerSera Therapeutics, Puma Biotechnology. Attending meeting and/or travel: Eli Lilly and Company, Grail Inc. José Angel García-Sáenz: Grants or contracts: Stemline Menarini, Jazz Pharmaceutical. Consulting fees: Stemline Menarini, Eli Lilly and Company. Advisory Board: Daiichi Sankyo, AstraZeneca, Eli Lilly and Company, Novartis, Gilead. Speaker's bureau: Eli Lilly and Company, Novartis, Astrofarma. Research funding: AstraZeneca. Attending meeting and/or travel: Roche, Novartis, Daiichi-Sankyo. Don S. Dizon: Consulting fees: GSK, Clovis and Pharma, Astra Zeneca, Kronos Biotech. Stock: Doximity, Midi Health. Els Van Nieuwenhuysen: Research funding: Eli Lilly and Company. Yujia Li; Shawn T. Estrem; Bastien Nguyen; Francesca Bacchion; Roohi Ismail-Khan are employees and stock owners of Eli Lilly and Company. Komal Jhaveri: Institutional research funding:Novartis, Genentech, Debiopharm group, ADC therapeutics, Pfizer, Novita Pharmaceuticals, Clovis oncology, Eli Lilly and Company, Zymeworks, Immunomedics, Puma Biotechnology, VelosBio/Merck, AstraZeneca, Context Therapeutics, Scorpion Therapeutics, Blueprint Medicines. Consulting fees: Novartis, Pfizer, AstraZeneca, Jounce Therapeutics, Synthon, Intellisphere, Bristol Myers Squibb, Genetench, Abbvie, Eli Lilly and Company, BluePrint Medicines, Seagen, Daiichi-Sankyo, Biotheranostics, Sun Pharma Advanced Research Company, Taiho Oncology, Sanofi, Gilead Sciences, Scorpion Therapeutics. Attending meeting and/or travel: Taiho Pharmaceutical, Jounce therapeutics, Pfizer, AstraZeneca, Intellisphere, Eli Lilly and Company, Gilead Sciences, Genetench/Roche. Kalyan Banda: Institutional research funding: Eli Lilly and Company, MorphoSys, Regeneron, Kineta, Pfizer; Honoraria: American Society for Clinical Oncology; Advisory Board: Astra Zeneca, Immunogen; Attending meeting and/or travel: American Society for Clinical Oncology. The other authors have completed conflict of interest forms and do not have potential conflicts of interest related to subject matter discussed in this manuscript to declare., (Copyright © 2024. Published by Elsevier Inc.)

With buildings representing a substantial portion of global energy consumption, exploring alternatives to traditional fossil fuel-based heating and cooling systems is critical. Thermoelectricity offers a promising solution by converting temperature differentials into electrical voltage or vice versa, enabling efficient indoor thermal regulation. This paper presents a comprehensive investigation into the integration of thermoelectric wall systems for sustainable building climate control through numerical simulations and experimental analyses. Numerical simulations using computational fluid dynamics (CFD) techniques were conducted to model fluid flow and heat transfer within the thermoelectric wall systems under various operating conditions. These simulations provided insights into the system's thermal behavior, which were validated through experimental setups designed to measure temperature differentials, airflow rates, and power consumption. The results showed that power consumption is directly correlated with electrical current, ranging from 0.19 W to 77.4 W as the current increased from 0.1 A to 2 A. Additionally, the heat absorbed by the system increased significantly with electrical current, by 706-1044%, depending on the air velocity. The thermal energy released from the hot side of the thermoelectric modules also rose substantially, ranging from 9850 to 5285% with increasing electrical current, and from 275 to 51% with higher air velocities. Moreover, increasing air velocity led to a 6.78-9.37% reduction in power consumption for currents between 0.1 A and 2 A. The coefficient of performance (COP) analysis revealed that optimizing both electrical current and air velocity is essential for maximizing system efficiency. While fan power consumption reduces COP at higher air velocities, neglecting fan power consumption results in COP improvements ranging from 6.5 × 10⁻⁴ to 49.0%. These findings highlight the potential of thermoelectric wall systems to enhance indoor comfort and energy efficiency in buildings., (© 2024. The Author(s).)

Objectives: This study investigated the association of MSX1 gene variants rs3821949 and rs12532 with nonsyndromic cleft lip and/or palate (NSCL/P) in the Pakistani population., Design: Comparative cross-sectional study. Setting: Multicenter of CL/P malformation. Patients/Participants: Unrelated Non-Syndromic cleft Lip/Palate patients and healthy controls were enrolled., Methods: One hundred ( n  = 100) subjects with NSCL/P and n  = 50 unrelated healthy controls were enrolled in a multicenter comparative cross-sectional study. A tetra amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) was performed to analyze MSXI gene single nucleotide variants (SNVs)., Results: Among 100 NSCL/P subjects, the majority were males (56%; male: female = 1.27: 1). Most of the cases (74%) had cleft lip and palate (CLP) compared to isolated clefts. Genotyping of MSX1 gene variant rs3821949 showed an increased risk for NSCL/P in various genetic models ( P <  0.0001), and the A allele exhibited a more than 4-fold increased risk among cases (OR = 4.22: 95% CI = 2.16-8.22; P <  0.0001). Our investigation found no significant difference between the rs12532 variation and NSCL/P., Conclusion: Our study findings suggest that MSX1 gene variants may increase predisposition to NSCL/P in the Pakistani population. Further studies comprising large samples are required to identify the genetic aetiology of NSCL/P among our people., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.