bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sperm epigenetics and male infertility: unraveling the molecular puzzle
Authors: Hosseini Maryam , Khalafiyan Anis , Zare Mohammadreza , Karimzadeh Haniye , Bahrami Basireh , Hammami Behnaz , Kazemi Mohammad 
Published: June 2024

Abstract
Background
The prevalence of infertility among couples is estimated to range from 8 to 12%. A paradigm shift has occurred in understanding of infertility, challenging the notion that it predominantly affects women. It is now acknowledged that a significant proportion, if not the majority, of infertility cases can be attributed to male-related factors. Various elements contribute to male reproductive impairments, including aberrant sperm production caused by pituitary malfunction, testicular malignancies, aplastic germ cells, varicocele, and environmental factors.

Main body
The epigenetic profile of mammalian sperm is distinctive and specialized. Various epigenetic factors regulate genes across different levels in sperm, thereby affecting its function. Changes in sperm epigenetics, potentially influenced by factors such as environmental exposures, could contribute to the development of male infertility.

Conclusion
In conclusion, this review investigates the latest studies pertaining to the mechanisms of epigenetic changes that occur in sperm cells and their association with male reproductive issues.
Symptom domains and psychosocial functioning in borderline personality disorder
Authors: Culina Ines , Ranjbar Setareh , Maillard Pauline , Martin-Soelch Chantal , Berney Sylvie , Kolly Stéphane , André Jérémie , Conus Philippe , Kramer Ueli 
Published: June 2024

Abstract
Background
Borderline personality disorder (BPD) is often characterized by severe functional impairment, even after a decrease in symptoms. A comprehensive understanding of psychosocial functioning in BPD is necessary to tailor treatment offer, which should address relevant aspects of daily life. The aims of the present study are to (1) conduct a cross-sectional comparison of functioning of a group with BPD and a non-BPD clinical comparison group at service entry, and to (2) assess the relationship between intensity of BPD symptom domains and psychosocial functioning.

Methods
The sample consists of N = 65 participants with BPD and N = 57 participants from the clinical comparison group without BPD (non-BPD group). The Revised Borderline Follow-up Interview (BFI-R) was used to evaluate psychosocial functioning and the Revised Diagnostic Interview for Borderlines (DIB-R) to assess BPD symptoms. Linear, logistic, and multinomial regression models were run separately for each aspect of functioning as a function of BPD status or BPD symptom domains.

Results
Only 23% of participants in the BPD group fulfilled criteria for good overall psychosocial functioning, compared to 53% in the non-BPD group. Furthermore, participants in the BPD group were less likely to have completed a high number of years of education, to work consistently, to be financially independent, to be in a cohabiting relationship and have a good relationship with parents. In addition, various links were identified between BPD symptom domains and functional impairments.

Conclusions
Consistent with prior research, the main impairments in functioning in the BPD group are found in the educational and vocational domains. Though some domains show impairment, others, like friendships, may act as potential resources. Further investigation on the relationships with symptom domains is required.
Epigenetic targets of Janus kinase inhibitors are linked to genetic risks of rheumatoid arthritis
Authors: Tsuchiya Haruka , Ota Mineto , Takahashi Haruka , Hatano Hiroaki , Ogawa Megumi , Nakajima Sotaro , Yoshihara Risa , Okamura Tomohisa , Sumitomo Shuji , Fujio Keishi 
Published: June 2024

Abstract
Background
Current strategies that target cytokines (e.g., tumor necrosis factor (TNF)-α), or signaling molecules (e.g., Janus kinase (JAK)) have advanced the management for allergies and autoimmune diseases. Nevertheless, the molecular mechanism that underpins its clinical efficacy have largely remained elusive, especially in the local tissue environment. Here, we aimed to identify the genetic, epigenetic, and immunological targets of JAK inhibitors (JAKis), focusing on their effects on synovial fibroblasts (SFs), the major local effectors associated with destructive joint inflammation in rheumatoid arthritis (RA).

Methods
SFs were activated by cytokines related to inflammation in RA, and were treated with three types of JAKis or a TNF-α inhibitor (TNFi). Dynamic changes in transcriptome and chromatin accessibility were profiled across samples to identify drug targets. Furthermore, the putative targets were validated using luciferase assays and clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing.

Results
We found that both JAKis and the TNFi targeted the inflammatory module including IL6. Conversely, specific gene signatures that were preferentially inhibited by either of the drug classes were identified. Strikingly, RA risk enhancers for CD40 and TRAF1 were distinctively regulated by JAKis and the TNFi. We performed luciferase assays and CRISPR-based genome editing, and successfully fine-mapped the single causal variants in these loci, rs6074022-CD40 and rs7021049-TRAF1.

Conclusions
JAKis and the TNFi had a direct impact on different RA risk enhancers, and we identified nucleotide-resolution targets for both drugs. Distinctive targets of clinically effective drugs could be useful for tailoring the application of these drugs and future design of more efficient treatment strategies.
Pomegranate extract-loaded surfactant-free zein nanoparticles as a promising green approach for hepatic cancer: optimization and in vitro cytotoxicity
Authors: Mohsen Salma , Bakr Mohamed Mofreh , ElDegwy Mohamed A. , Abouhussein Dalia M. N. , Fares Ahmed R. , ElMeshad Aliaa N. 
Published: June 2024

Abstract
Background
Hepatic cancer endures a major health scourge as the consequence of a high incidence of > 1 million cases by 2025. Plant-based products are typically effective in ameliorating health conditions. Pomegranate peel extract (PE) with its high polyphenolic content has anticancer effects against different types of cancer. Herein, we aimed to maximize the PE chemotherapeutic efficacy by loading it in a suitable delivery system to overcome the limitations of PE, to control its release and to achieve liver targeting.

Method
A nanoprecipitation procedure was adopted to incorporate PE into biodegradable and biocompatible natural polymeric zein (ZN)-based nanoparticles (NPs) (PE-ZN NPs). A full factorial design (22 × 31) was developed to study the effects of the formulation variables, namely pH of dispersion, PE-to-ZN ratio and surfactant concentration.

Results
The optimization revealed a surfactant-free stable PE-ZN NPs formula with a small particle size of 99.5 ± 6.43 nm, high PE encapsulation efficiency % of 99.31% ± 3.64 (w/w) and controlled release of PE over 24 h.

Conclusion
Moreover, the cytotoxicity of the optimum formula against hepatic cancer HepG2 cell lines was assessed and attained about a 2.5-fold reduction in the inhibitory concentration (IC50) values compared to the free PE affording a promising green platform to combat hepatic cancer.

Graphical abstract
The evolution and future of eye movement desensitisation and reprocessing therapy
Authors: Miller Paul W. 
Published: June 2024

SUMMARYEye movement desensitisation and reprocessing (EMDR), a therapy initially developed by Dr Francine Shapiro for treating post-traumatic stress disorder, has broadened its scope to include other forms of stress and trauma, even showing promise for physical health conditions. This commentary on a series of three articles on EMDR in this journal outlines the therapy's underlying theoretical model, adaptive information processing (AIP), which involves trauma-focused case conceptualisation. It also introduces the work of the EMDR Council of Scholars, which identified three categories of treatment: EMDR psychotherapy, EMDR treatment protocols and EMDR-derived techniques. Finally, it considers EMDR training and credentialing and the aim of current leaders in the EMDR community to solidify EMDR's standing as a scientifically validated, front-line trauma therapy, while honouring Shapiro's legacy of striving to end the cycle of violence, especially in low- and middle-income countries.
Influence of cognitive reserve on risk of depression and subsequent dementia: A large community-based longitudinal study
Authors: Yang Wenzhe , Wang Jiao , Dove Abigail , Yang Yonghua , Qi Xiuying , Guitart-Masip Marc , Papenberg Goran , Xu Weili 
Published: June 2024

Abstract

Background
Cognitive reserve (CR) has been linked to dementia, yet its influence on the risk of depression and related outcomes remains unknown. We aimed to examine the association of CR with depression and subsequent dementia or death, and to assess the extent to which CR is related to depression-free survival.

Methods
Within the UK Biobank, 436,232 participants free of depression and dementia were followed. A comprehensive CR indicator (low, moderate, and high) was created using latent class analysis based on information on education, occupation, mentally passive sedentary behavior, social connection, confiding with others, and leisure activities. Depression, dementia, and survival status were ascertained through self-reported medical history and/or linkages to medical records. Data were analyzed using multi-state Markov model and Laplace regression.

Results
Over a median follow-up of 12.96 years, 16,560 individuals developed depression (including 617 with subsequent dementia) and 28,655 died. In multivariable multi-state models, compared with low CR, high CR was associated with lower risk of depression (hazard ratio 0.53 [95% confidence interval 0.51–0.56]) and lower risk of post-depression dementia (0.55 [0.34–0.88]) or death (0.69 [0.55–0.88]) in middle-aged adults (aged <60 years). In Laplace regression, the depression-free survival time was prolonged by 2.77 (2.58–2.96) years in participants with high compared to low CR.

Conclusions
High CR is associated with lower risks of depression and subsequent transitions to dementia and death, particularly in middle age. High CR may prolong depression-free survival. Our findings highlight the importance of enhancing CR in the prevention and prognosis of depression.
Impact of prior anticancer treatments on palbociclib (PAL) clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer (ABC) in real-world settings.
Authors: Rocque Gabrielle Betty , Blum Joanne Lorraine , Ji Yan , Pluard Timothy J. , Migas John , Lakhanpal Shailendra , Jepsen Erin Stephany , Wang Yao , Montelongo Monica Z. , Zhang Zhe , Gauthier Eric Roland , Tripathy Debashish 
Published: June 2024

1055 Background: Cyclin-dependent kinase 4/6 inhibitors (eg, PAL) combined with endocrine therapy (ET) is a standard of care for patients with HR+/HER2− ABC. The impact of prior anticancer treatments on clinical outcomes of patients with HR+/HER− ABC treated with palbociclib in routine care is not well known and was investigated in the POLARIS study. Methods: POLARIS is a prospective, observational, multicenter, real-world study in the US and Canada. Enrolled patients were adults (≥ 18 y) with HR+/HER2− ABC who received PAL + ET as standard of care. Real-world progression-free survival (rwPFS) and overall survival (OS) were described by prior treatment. Results: A total of 1250 patients were enrolled. Median age was 64 years (range, 22–97), 67.9% had recurrent disease, and 72.1% received PAL as first-line treatment (1LOT) vs 27.9% as ≥ 2LOT. Prior anticancer therapies (1LOT: adjuvant/neoadjuvant setting; ≥ 2LOT: metastatic setting) were received by 912 patients (73.0%), which included ET-alone (n=254), chemotherapy-alone (n=235), chemotherapy + ET (n=338) or other (n=85). The median follow-up duration was 35.7 months for rwPFS and 39.1 months for OS. In 1LOT, both rwPFS and OS were numerically shorter for patients who received prior chemotherapy (either alone or with ET) when compared with patients who received ET-alone or had no prior therapy (Table). In ≥ 2LOT, patients who received prior chemotherapy-alone or ET-alone had comparable rwPFS, which was numerically longer than for patients with prior chemotherapy + ET; OS was comparable regardless of prior treatment. Conclusions: Overall, patients with HR+/HER2− ABC with prior chemotherapy receipt tended to have shorter clinical benefit. Regardless of LOT, numerically longer rwPFS was achieved in patients who received prior ET-alone. In 1LOT, OS was longer in patients who received prior ET-alone while in ≥ 2LOT, OS was comparable across prior treatment subgroups. Small sample sizes of some ≥ 2LOT subgroups as well as observational nature of the study may limit interpretation. [Table: see text]
Interim analysis (IA) of the giredestrant (G) + everolimus (EVERO) arm in MORPHEUS Breast Cancer (BC): A phase I/II study of G treatment (tx) combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative, locally advanced/metastatic BC (LA/mBC).
Authors: Wander Seth Andrew , Stemmer Salomon M. , Rugo Hope S. , Im Seock-Ah , Lau Peter Kar Han , Paluch-Shimon Shani , Cahuzac Clélia , Collier Annie , Shah Mona D. , Ngo Huy X. , Schwab Richard B. , Zhu Jing , Oliveira Mafalda 
Published: June 2024

1059 Background: Endocrine therapy (ET) + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is a therapeutic mainstay for first-line tx of ER+ mBC. Finding effective ET combinations after progression remains a challenge; however, targeting the Akt/mTOR pathway is a promising approach. G is a highly potent, non-steroidal, oral (PO), selective ER antagonist and degrader that is well tolerated and achieves robust ER occupancy. EVERO is an approved mTOR inhibitor. Here, we present a 16-week IA of the G + EVERO arm in MORPHEUS BC (NCT04802759). Methods: Eligible pts with disease progression on 1–2 lines of ET (including a CDK4/6i) for LA/mBC were randomized 1:6 to receive G (30 mg PO daily [QD]) or G + EVERO (10 mg PO QD) until disease progression (PD)/unacceptable toxicity. The study was not designed to make explicit power and type I error considerations for a hypothesis test. Primary endpoints were safety and objective response rate (ORR); other endpoints included progression-free survival (PFS), overall survival, clinical benefit rate, disease control rate (DCR), duration of response, and pharmacokinetics. Steroid mouthwash was recommended for prophylaxis or treatment. Genetic alterations were defined using baseline circulating tumor DNA. Results: Results for the G arm have been presented previously and are not included here. As of July 24, 2023, 15 pts were enrolled in the G + EVERO arm: 66.7% and 33.3% received 1–2 prior lines of therapy for LA/mBC, respectively; 26.7% had prior fulvestrant, and 73.3% had liver metastasis at enrollment. One pt had prior capecitabine. Safety data are in the table. Confirmed ORR in the G + EVERO arm was 26.7% (n = 4). Partial responses were reported in 26.7% of pts (n = 4; all had ESR1 mutations, 1 also had an Akt pathway mutation), 46.7% of pts (n = 7) had stable disease, and the DCR was 53.3% (n = 8). Median PFS was not reached at data cutoff. No clinically relevant drug–drug interactions were observed. Conclusions: Safety of G + EVERO was aligned with the individual safety profile of each drug with no overlapping toxicities or new safety signals seen. An encouraging efficacy signal was observed with G + EVERO in pts with PD on 1–2 lines of ET (including a CDK4/6i). G + EVERO is being further investigated in the Phase III evERA BC trial (NCT05306340). Clinical trial information: NCT04802759 . [Table: see text]
SurvivorCHIP: Evaluation of clonal hematopoiesis in women treated for breast cancer.
Authors: Bahr Reem , Nosiri Chidera , Gui Gege , Mukherjee Devdeep , Hegde Pranay , Malloy Stacy K , Shastri Preeti , Peravali Monica , Chitalia Ami , Gallagher Christopher , DeStefano Christin , Dillon Laura W. , Shenoy Aarthi G. , Hourigan Christopher S. 
Published: June 2024

1082 Background: Clonal hematopoiesis (CH) has been associated with reduced overall survival and is shown to be increased in patients with solid tumors after receiving chemotherapy and radiotherapy. However, the clinical implications of these observations have not been prospectively evaluated among different racial groups. This study was initiated in an urban cancer center to study CH rates before and after cancer therapy in a racially diverse population. Methods: Women aged ≥18 with newly diagnosed non-metastatic breast cancer provided written informed consent for this IRB approved study. Error-corrected DNA-sequencing was performed on 50ng gDNA isolated from blood prior to (pre-Tx), and following (post-Tx), chemotherapy(C), radiotherapy(R), and/or endocrine (E) therapy. Pathogenic or likely pathogenic variants were determined in regions recurrently mutated in CH. Results: 56 patients, median age 59.5y (29-82), provided both pre-Tx and post-Tx blood samples. Median BMI was 31.2 (range: 21.1-52.7) with 48 (85%) overweight (BMI≥25) and 33 (59%) obese (BMI≥30). 21 (38%) were active smokers. CH variants with an allele frequency (VAF) ≥2% were identified in 8 (14%) patients pre-Tx, most commonly DNMT3A (5 patients). For those with CH, median age was 64y (49-80) and 5 were active smokers. BMI was not statistically associated with pre-Tx CH in this cohort. 48 (86%) of the patients self-identified as African American and 7 (15%) had CH pre-Tx. Post-Tx, 10 patients had CH (18%), persistent from pre-Tx in 7. Of those with different CH classifications pre- and post-Tx, 1 had DNMT3A CH pre-Tx no longer detectable post-Tx (CRE), 2 had DNMT3A CH detectable at VAF ≥2% post-Tx (1 with CH undetected prior to RE Tx, 1 with the same DNMT3A variant at 1.2% VAF prior to CRE), and a 3rd had a ATRX variant increase from 1.5% to 2.1% VAF post-Tx (CRE). To investigate potential clinical implications of CH post-Tx, we utilized the clonal hematopoiesis risk score (CHRS) calculator which aims to predict risk of developing MDS and AML (Weeks et al, NEJM). Pre-Tx, 6 of the CH patients were classified as low risk, and 2 as intermediate risk. Patients developing CH post-Tx were all classified as low risk. Risk scores remained otherwise unchanged. At a median follow up of 2y, none of the patients in this study have been reported to develop MDS or AML. Conclusions: In this cohort of patients with newly diagnosed non-metastatic breast cancer, we did not find evidence to justify clinical screening/monitoring for CH before and after therapy.
Prognosis and tumor-infiltrating lymphocytes (TILs) in estrogen receptor (ER)-low metastatic breast cancer (MBC): Analysis from a large multi-institutional cohort and the TONIC phase II trial with nivolumab.
Authors: Miglietta Federica , Vernieri Claudio , de Graaf Manon , Secomandi Fabio , Cacciatore Matilde , Botticelli Andrea , Vingiani Andrea , Fotia Giuseppe , Griguolo Gaia , Giarratano Tommaso , Pellegrini Valerio , Iannaccone Daniela , Porra Francesca , Fassan Matteo , Pruneri Giancarlo , Dei Tos Angelo Paolo , Guarneri Valentina , Kok Marleen , Dieci Maria Vittoria 
Published: June 2024

1100 Background: Although 1% as ER cutoff to discriminate ER+/HER2- from triple-negative (TN) BC serves the purpose of maximizing access to endocrine therapy, it may be suboptimally informative in terms of prognosis and immune checkpoint inhibitor (ICI) benefit. In the early setting, we reported that ER-low BC (ER 1-9%/HER2-) is immunologically and prognostically similar to TN (ER 0%) [Massa, 2023]. Here we focus on MBC and aim to assess prognosis of ER-low BC, including the conversion from ER+(≥10%)/HER2- to ER-low at relapse. We also compared ER-low and TN in terms of outcome after ICI, and TILs. Methods: We included two cohorts of MBC patients (pts): a multicentric retrospective cohort and pts with ER<10%/HER2- MBC enrolled in the TONIC trial testing nivolumab +/- induction therapy. All pts had ER and HER2 status assessed on metastatic tumor lesion; in the retrospective cohort ER and HER2 status on primary tumor was also available. Survival endpoints in the retrospective cohort: overall survival (OS, from BC diagnosis), post-relapse survival (PRS, from BC relapse). Exploratory endpoints from the TONIC trial: clinical benefit rate (CBR), OS and PFS (both from randomization). TILs were assessed on MBC samples (both cohorts) and on matched primary tumor (retrospective cohort). Results: We included 1112 pts in the retrospective cohort: the prevalence of ER-low BC was 3.6% in primary tumor and 5.9% in MBC lesions. In the TONIC trial, 15/110 pts had ER-low MBC. In the retrospective cohort, ER-low and TN MBC showed similar outcome, and significantly unfavorable vs ER+/HER2- MBC (Table). Among pts with ER+/HER2- primary BC, 6.7% converted to ER-low and 14.7% to TN at relapse. ER+/HER2- BC pts converting to ER-low had similar outcome than those converted to TN, and significantly poorer than pts with stable ER+/HER2- (Table). In the TONIC trial, ER-low MBC pts, compared to TN, showed similar response to ICI (CBR: 20.0% vs 22.1%, p=1), similar PFS and numerically worse OS (Table). TIL levels on MBC samples were similar between ER-low and TN both in the retrospective (median: 6% vs 5%, p=0.83) and the TONIC cohorts (median: 5.5% vs 5.0%, p=0.56) and were higher than ER+/HER2- (median: 3%). Conclusions: We confirmed that ER-low and TN MBC show similar poor outcome and the shift from ER+/HER2- to ER-low has a comparable unfavorable prognostic impact compared to conversion to TN. Our results support the hypothesis that ER-low and TN are immunologically akin and similarly prone to respond to ICI. [Table: see text]