bluuebunny/crossref_metadata_2025 huggingface dataset:
Attitudes of female market vendors of reproductive age towards use of mobile phones and access to family planning self-care interventions in Northern Uganda: a cross-sectional study
Authors: Walter Yagos Onen , Atim Pamela , Amone Derrick , Peter Alarakol Simon , Tabo Geoffrey Olok
Published: June 2024

Background

Mobile phones are potential digital technologies for accessing family planning self-care interventions. However, their utilization could be possible if women of reproductive age have positive attitudes towards the use of this technology for healthcare purposes. This study aimed to examine the relationship between attitudes towards the use of mobile phones and access to family planning self-care interventions among female market vendors of reproductive age in northern Uganda.

Methods

A cross-sectional survey design was used. Two hundred and five randomly selected female vendors from the Gulu city main market participated. A structured researcher-administered questionnaire was used to collect the data. Descriptive statistics and standard multiple regression were performed, and the data were analysed using SPSS software version 15.

Results

Of the 205 participants, 112 (54.6%) reported using smartphones, and 147 (71.7%) were aware of family planning self-care interventions. Participants had moderate attitudes towards access to family planning self-care interventions (mean = 3.18), positive attitudes towards ease of use (mean = 3.31) and usefulness of mobile phones (mean = 3.30), strong positive attitudes towards privacy (mean = 4.04), and skills associated with using mobile phones (mean = 4.04). Furthermore, significant positive relationships existed between ease of use (pvalue = 0.000), skills (pvalue = 0.001), privacy (pvalue = 0.002) and access to family planning self-care interventions. There was, however, an insignificant positive relationship between mobile phone usefulness and access to family planning self-care interventions (pvalue = 0.189).

Conclusions

Participants’ positive attitudes towards the use of mobile phones could lead to access to FP self-care interventions, although uncertainty about the usefulness of the use of mobile phones for accessing FP self-care interventions exists. It is therefore important for healthcare practitioners, health development partners and the government to encourage and integrate the use of mHealth into regular FP self-care services and promotional activities while targeting underserved communities in Uganda.
Dynamics of pulmonary mucosal cytotoxic CD8 T-cells in people living with HIV under suppressive antiretroviral therapy
Authors: Alexandrova Yulia , Yero Alexis , Olivenstein Ronald , Orlova Marianna , Schurr Erwin , Estaquier Jerome , Costiniuk Cecilia T. , Jenabian Mohammad-Ali
Published: June 2024

Background

Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their smoking status. Cytotoxic CD8 T-cells are likely implicated in this phenomenon and may act as a double-edged sword. While being essential in viral infection control, their hyperactivation can also contribute to lung mucosal tissue damage. The effects of HIV and smoking on pulmonary mucosal CD8 T-cell dynamics has been a neglected area of research, which we address herein.

Methods

Bronchoalveolar lavage (BAL) fluid were obtained from ART-treated PLWH (median duration of supressed viral load: 9 years; smokers: n = 14; non-smokers: n = 21) and HIV-uninfected controls (smokers: n = 11; non-smokers: n = 20) without any respiratory symptoms or active infection. Lymphocytes were isolated and CD8 T-cell subsets and homing markers were characterized by multiparametric flow cytometry.

Results

Both smoking and HIV infection were independently associated with a significant increase in frequencies of total pulmonary mucosal CD8 T-cell. BAL CD8 T-cells were primarily CD69 + expressing CD103 and/or CD49a, at least one of the two granzymes (GzmA/GzmB), and little Perforin. Higher expression levels of CD103, CD69, and GzmB were observed in smokers versus non-smokers. The ex vivo phenotype of GzmA + and GzmB + cells revealed increased expression of CD103 and CXCR6 in smokers, while PLWH displayed elevated levels of CX3CR1 compared to controls.

Conclusion

Smoking and HIV could promote cytotoxic CD8 T-cell retention in small airways through different mechanisms. Smoking likely increases recruitment and retention of GzmB + CD8 Trm via CXCR6 and CD103. Heightened CX3CR1 expression could be associated with CD8 non-Trm recruitment from the periphery in PLWH.
Exploring the interaction and impact of probiotic and commensal bacteria on vitamins, minerals and short chain fatty acids metabolism
Authors: Bermúdez-Humarán Luis G. , Chassaing Benoit , Langella Philippe
Published: June 2024

There is increasing evidence that probiotic and commensal bacteria play a role in substrate metabolism, energy harvesting and intestinal homeostasis, and may exert immunomodulatory activities on human health. In addition, recent research suggests that these microorganisms interact with vitamins and minerals, promoting intestinal and metabolic well-being while producing vital microbial metabolites such as short-chain fatty acids (SCFAs). In this regard, there is a flourishing field exploring the intricate dynamics between vitamins, minerals, SCFAs, and commensal/probiotic interactions. In this review, we summarize some of the major hypotheses beyond the mechanisms by which commensals/probiotics impact gut health and their additional effects on the absorption and metabolism of vitamins, minerals, and SCFAs. Our analysis includes comprehensive review of existing evidence from preclinical and clinical studies, with particular focus on the potential interaction between commensals/probiotics and micronutrients. Finally, we highlight knowledge gaps and outline directions for future research in this evolving field.
Management of internal iliac and obturator lymph nodes in mid-low rectal cancer
Authors: Xiao Tixian , Chen Jianan , Liu Qian
Published: June 2024

In rectal cancer treatment, the diagnosis and management of lateral pelvic lymph nodes (LLN) are critical for preventing local recurrence. Over time, scholars have reached a consensus: when imaging suggests LLN metastasis, combining neoadjuvant chemoradiotherapy (nCRT) with selective LLN dissection (LLND) can mitigate the risk of recurrence. Selective LLND typically encompasses lymph nodes in the internal iliac and obturator regions. Recent studies emphasize distinctions between internal iliac and obturator lymph nodes regarding prognosis and treatment outcomes, prompting the need for differentiated diagnostic and treatment approaches.
KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination
Authors: Rosell Rafael , Jantus-Lewintre Eloisa , Cao Peng , Cai Xueting , Xing Baojuan , Ito Masaoki , Gomez-Vazquez Jose Luis , Marco-Jordán Mireia , Calabuig-Fariñas Silvia , Cardona Andrés Felipe , Codony-Servat Jordi , Gonzalez Jessica , València-Clua Kevin , Aguilar Andrés , Pedraz-Valdunciel Carlos , Dantes Zahra , Jain Anisha , Chandan S , Molina-Vila Miguel Angel , Arrieta Oscar , Ferrero Macarena , Camps Carlos , González-Cao Maria
Published: June 2024

Background

KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions.

Methods

Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model.

Results

Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression.

Conclusions

We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.
Dual anti-angiogenic and anti-inflammatory action of tRNA-Cys-5-0007 in ocular vascular disease
Authors: Ma Yan , Zhang Ying , Zhang Hui-Ying , Zhao Ya , Li Xiu-Miao , Jiang Yi-Fei , Yao Mu-Di , Jiang Qin , Yan Biao
Published: June 2024

Background

Intravitreal injections of angiogenesis inhibitors have proved efficacious in the majority of patients with ocular angiogenesis. However, one-fourth of all treated patients fail to derive benefits from intravitreal injections. tRNA-derived small RNA (tsRNA) emerges as a crucial class of non-coding RNA molecules, orchestrating key roles in the progression of human diseases by modulating multiple targets. Through our prior sequencing analyses and bioinformatics predictions, tRNA-Cys-5-0007 has shown as a potential regulator of ocular angiogenesis. This study endeavors to elucidate the precise role of tRNA-Cys-5-0007 in the context of ocular angiogenesis.

Methods

Quantitative reverse transcription PCR (qRT-PCR) assays were employed to detect tRNA-Cys-5-0007expression. EdU assays, sprouting assays, transwell assays, and Matrigel assays were conducted to elucidate the involvement of tRNA-Cys-5-0007 in endothelial angiogenic effects. STZ-induced diabetic model, OIR model, and laser-induced CNV model were utilized to replicate the pivotal features of ocular vascular diseases and evaluate the influence of tRNA-Cys-5-0007 on ocular angiogenesis and inflammatory responses. Bioinformatics analysis, luciferase activity assays, RNA pull-down assays, and in vitro studies were employed to elucidate the anti-angiogenic mechanism of tRNA-Cys-5-0007. Exosomal formulation was employed to enhance the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007.

Results

tRNA-Cys-5-0007 expression was down-regulated under angiogenic conditions. Conversely, tRNA-Cys-5-0007 overexpression exhibited anti-angiogenic effects in retinal endothelial cells, as evidenced by reduced proliferation, sprouting, migration, and tube formation abilities. In diabetic, laser-induced CNV, and OIR models, tRNA-Cys-5-0007 overexpression led to decreased ocular vessel leakage, inhibited angiogenesis, and reduced ocular inflammation. Mechanistically, these effects were attributed to the targeting of vascular endothelial growth factor A (VEGFA) and TGF-β1 by tRNA-Cys-5-0007. The utilization of an exosomal formulation further potentiated the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007.

Conclusions

Concurrent targeting of tRNA-Cys-5-0007 for anti-angiogenic and anti-inflammatory therapy holds promise for enhancing the effectiveness of current anti-angiogenic therapy.
Immune cell phenotypes and mortality in the Framingham Heart Study
Authors: Ragab Ahmed A. Y. , Doyle Margaret F. , Chen Jiachen , Fang Yuan , Lunetta Kathryn L. , Murabito Joanne M.
Published: June 2024

Background

Global life expectancy is rising, with the 60 + age group projected to hit 2 billion by 2050. Aging impacts the immune system. A notable marker of immune system aging is the presence of Aging-Related Immune Cell Phenotypes (ARIPs). Despite their importance, links between immune cell phenotypes including ARIPs and mortality are underexplored. We prospectively investigated 16 different immune cell phenotypes using flow cytometry and IL-6 in relation to survival outcome among dementia-free Framingham Heart Study (FHS) offspring cohort participants who attended the seventh exam (1998–2001).

Results

Among 996 participants (mean age 62 years, range 40 to 88 years, 52% female), the 19-year survival rate was 65%. Adjusting for age, sex, and cytomegalovirus (CMV) serostatus, higher CD4/CD8 and Tc17/CD8 + Treg ratios were significantly associated with lower all-cause mortality (HR: 0.86 [0.76–0.96], 0.84 [0.74–0.94], respectively), while higher CD8 regulatory cell levels (CD8 + CD25 + FoxP3 +) were associated with increased all-cause mortality risk (HR = 1.17, [1.03–1.32]). Elevated IL-6 levels correlated with higher all-cause, cardiovascular, and non-cardiovascular mortality (HR = 1.43 [1.26–1.62], 1.70 [1.31–2.21], and 1.36 [1.18–1.57], respectively). However, after adjusting for cardiovascular risk factors and prevalent cancer alongside age, sex, and CMV, immune cell phenotypes were no longer associated with mortality in our cohort. Nonetheless, IL-6 remained significantly associated with all-cause and cardiovascular mortality (HRs: 1.3 [1.13–1.49], 1.5 [1.12–1.99], respectively).

Conclusions

In 19-year follow-up, higher Tc17/CD8 + Treg and CD4/CD8 ratios were associated with lower all-cause mortality, while the CD8 + CD25 + FoxP3 + (CD8 + Treg) phenotype showed increased risk. Elevated IL-6 levels consistently correlated with amplified mortality risks. These findings highlight the links between immune phenotypes and mortality, suggesting implications for future research and clinical considerations.
Advances in SIRT3 involvement in regulating autophagy-related mechanisms
Authors: Xi Shuangyun , Chen Weijun , Ke Yong
Published: June 2024

The silencing regulatory factor 2-like protein 3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+) dependent deacetylase located primarily in the mitochondria. This protein plays an important role in oxidative stress, energy metabolism, and autophagy in multicellular organisms. Autophagy (macroautophagy) is primarily a cytoprotective mechanism necessary for intracellular homeostasis and the synthesis, degradation, and recycling of cellular products. Autophagy can influence the progression of several neural, cardiac, hepatic, and renal diseases and can also contribute to the development of fibrosis, diabetes, and many types of cancer. Recent studies have shown that SIRT3 has an important role in regulating autophagy. Therefore in this study, we aimed to perform a literature review to summarize the role of SIRT3 in the regulation of cellular autophagy. The findings of this study could be used to identify new drug targets for SIRT3-related diseases.

Methods: A comprehensive literature review of the mechanism involved behind SIRT3 and autophagy-related diseases was performed. Relevant literature published in Pubmed and Web of Science up to July 2023 was identified using the keywords “silencing regulatory factor 2-like protein 3”, “SIRT3” and “autophagy”.
An essential gene signature of breast cancer metastasis reveals targetable pathways
Authors: Zhang Yiqun , Chen Fengju , Balic Marija , Creighton Chad J.
Published: June 2024

Background

The differential gene expression profile of metastatic versus primary breast tumors represents an avenue for discovering new or underappreciated pathways underscoring processes of metastasis. However, as tumor biopsy samples are a mixture of cancer and non-cancer cells, most differentially expressed genes in metastases would represent confounders involving sample biopsy site rather than cancer cell biology.

Methods

By paired analysis, we defined a top set of differentially expressed genes in breast cancer metastasis versus primary tumors using an RNA-sequencing dataset of 152 patients from The Breast International Group Aiming to Understand the Molecular Aberrations dataset (BIG-AURORA). To filter the genes higher in metastasis for genes essential for breast cancer proliferation, we incorporated CRISPR-based data from breast cancer cell lines.

Results

A significant fraction of genes with higher expression in metastasis versus paired primary were essential by CRISPR. These 264 genes represented an essential signature of breast cancer metastasis. In contrast, nonessential metastasis genes largely involved tumor biopsy site. The essential signature predicted breast cancer patient outcome based on primary tumor expression patterns. Pathways underlying the essential signature included proteasome degradation, the electron transport chain, oxidative phosphorylation, and cancer metabolic reprogramming. Transcription factors MYC, MAX, HDAC3, and HCFC1 each bound significant fractions of essential genes.

Conclusions

Associations involving the essential gene signature of breast cancer metastasis indicate true biological changes intrinsic to cancer cells, with important implications for applying existing therapies or developing alternate therapeutic approaches.
Colchicine to reduce coronavirus disease-19-related inflammation and cardiovascular complications in high-risk patients post-acute infection with SARS-COV-2—a study protocol for a randomized controlled trial
Authors: Thankachen Shani S. , Devasenapathy Niveditha , Bassi Abhinav , Ghosh Arpita , Arfin Sumaiya , Gummidi Balaji , Basheer Aneesh , Bangi Ashfak , Sahu Dibakar , Bhalla Ashish , Blesson Merlin , Jain Manish , Jha Vivekanand
Published: June 2024

Background

There is no known effective pharmacological therapy for long COVID, which is characterized by wide-ranging, multisystemic, fluctuating, or relapsing symptoms in a large proportion of survivors of acute COVID. This randomized controlled trial aims to assess the safety and efficacy of an anti-inflammatory agent colchicine, to reduce symptoms among those at high risk of developing long COVID.

Methods

This multi-centre, parallel arm, 1:1 individual randomized, placebo-controlled, double-blind superiority trial will enrol 350 individuals with persistent post-COVID symptoms. Participants will be randomized to either colchicine 0.5 mg once daily (< 70 kg) or twice daily (≥ 70 kg) or matched placebo for 26 weeks and will be followed up until 52 weeks after randomization. The primary trial objective is to demonstrate the superiority of colchicine over a placebo in improving distance walked in 6 min at 52 weeks from baseline. The secondary objectives are to assess the efficacy of colchicine compared to placebo with respect to lung function, inflammatory markers, constitutional symptoms, and mental health state. In a sub-sample of 100 participants, cardiac biomarkers of myocardial injury and myocardial oedema using MRI will be compared.

Discussion

Persistent inflammatory response following SARS-CoV-19 is one of the postulated pathophysiological mechanisms of long COVID. Colchicine, a low-cost anti-inflammatory agent, acts via multiple inflammatory pathways and has an established safety profile. This trial will generate evidence for an important health priority that can rapidly translate into practice.

Trial registration

This clinical trial has been registered prospectively on www.clinicaltrials.gov with registration CTRI/2021/11/038234 dated November 24, 2021.
Generalized music therapy to reduce neuroactive drug needs in critically ill patients. Study protocol for a randomized trial
Authors: Mistraletti Giovanni , Solinas Anna , Del Negro Silvia , Moreschi Carlotta , Terzoni Stefano , Ferrara Paolo , Negri Katerina , Calabretta Davide , Formenti Paolo , Formenti Angelo , Umbrello Michele
Published: June 2024

Background

Critically ill patients are exposed to several physical and emotional stressors, needing analgesic and sedative drugs to tolerate invasive procedures and the harsh intensive care unit (ICU) environment. However, this pharmacological therapy presents several side effects: guidelines suggest using a light sedation target, keeping critically ill patients calm, conscious, and cooperative. Personalized music therapy (MT) can reduce stress and anxiety, decreasing the need for drugs. The aim of the current investigation is to compare different approaches for MT in the ICU: a personalized approach, with music selected by patients/families and listened through headphones, or a generalized approach, with ambient music chosen by a music therapist and transmitted through speakers. Primary outcome: number of days “free from neuroactive drugs” in the first 28 days after ICU admission. Secondary outcomes: total amount of neuroactive drugs (midazolam, propofol, morphine, fentanyl, haloperidol), stress during ICU stay (sleep at night, anxiety and agitation, use of physical restraints, stressors evaluated at discharge), the feasibility of generalized MT (interruptions requested by staff members and patients/families).

Methods

Randomized, controlled trial with three groups of critically ill adults: a control group, without MT; a personalized MT group, with music for at least 2 h per day; a generalized MT group, with music for 12.5 h/day, subdivided into fifteen 50-min periods.

Discussion

One hundred fifty-three patients are expected to be enrolled. This publication presents the rationale and the study methods, particularly the strategies used to build the generalized MT playlist. From a preliminary analysis, generalized MT seems feasible in the ICU and is positively received by staff members, critically ill patients, and families.

Trial registration

ClinicalTrials.gov Identifier: NCT03280329. September 12, 2017.
Alterations of plasma circulating microRNAs in BALB/c mice with Toxocara canis visceral and cerebral larva migrans
Authors: Yang Yifan , Chen Yi , Zheng Zhiwan , Lin Lijun , Chen Xueqiu , Yang Chenyu , Zhong Die , Wu Haiyan , Xiong Zhiwei , Liu Sishi , Wang Tao , Yang Yi , Du Aifang , Ma Guangxu
Published: June 2024

Background

Human toxocariasis is a neglected parasitic disease characterised by the syndromes visceral, cerebral, and ocular larva migrans. This disease is caused by the migrating larvae of Toxocara roundworms from dogs and cats, affecting 1.4 billion people globally. Via extracellular vesicles (EVs), microRNAs have been demonstrated to play roles in host–parasite interactions and proposed as circulating biomarkers for the diagnosis and follow-up of parasitic diseases.

Methods

Small RNA-seq was conducted to identify miRNAs in the infective larvae of T. canis and plasma EV-containing preparations of infected BALB/c mice. Differential expression analysis and target prediction were performed to indicate miRNAs involved in host–parasite interactions and miRNAs associated with visceral and/or cerebral larva migrans in the infected mice. Quantitative real-time polymerase chain reaction (PCR) was used to amplify circulating miRNAs from the infected mice.

Results

This study reports host and parasite miRNAs in the plasma of BALB/c mice with visceral and cerebral larva migrans and demonstrates the alterations of these miRNAs during the migration of larvae from the livers through the lungs and to the brains of infected mice. After filtering unspecific changes in an irrelevant control, T. canis-derived miRNAs and T. canis infection-induced differential miRNAs are predicted to modulate genes consistently involved in mitogen-activated protein kinase (MAPK) signalling and pathways regulating axon guidance and pluripotency of stem in the infected mice with visceral and cerebral larva migrans. For these plasma circulating miRNAs predicted to be involved in host-parasite crosstalk, two murine miRNAs (miR-26b-5p and miR-122-5p) are experimentally verified to be responsive to larva migrans and represent circulating biomarker candidates for visceral and cerebral toxocariasis in BALB/c mice.

Conclusions

Our findings provide novel insights into the crosstalk of T. canis and the mammalian host via plasma circulating miRNAs, and prime agents and indicators for visceral and cerebral larva migrans. A deep understanding of these aspects will underpin the diagnosis and control of toxocariasis in humans and animals.

Graphical Abstract
Ectopic adrenocortical adenoma characterized by hypogonadism: a case report and review of the literature
Authors: Wang Zhihua , Zhong Xueyu , Yu Jiayu , Li Huiqing , Zheng Juan
Published: June 2024

Background

Currently, there is a scarcity of cases and diagnostic data regarding ectopic adrenocortical adenomas, particularly in relation to their impact on gonadal function and localization diagnostic techniques. We report a typical case of ectopic adrenocortical adenomas and the data of treatment follow-up, and review the literature of 31 available cases of ectopic adrenocortical adenomas.

Case presentation

A 27-year-old Chinese female patient was admitted to our hospital for hypertension, hyperglycaemia and primary amenorrhea. The patient was functionally diagnosed with ACTH-independent CS and hypogonadotropic hypogonadism. Radiological evaluations, including Computed Tomography (CT) and functional imaging, identified a mass at the left renal hilum. Histological assessments post-surgical excision confirmed the mass to be an ectopic adrenocortical adenoma. A subsequent 3-month follow-up showed no signs of disease recurrence, a swift recovery of the cortisol axis was observed, with a partial recuperation of the gonadal axis. Review: Our literature review shows that the most common ectopic areas of cortisol adenomas are renal hilum and hepatic region. The most positive biomarker is Melan A, and only a few cases have been diagnosed with functional localization.

Conclusion

Ectopic adrenocortical adenomas may be asymptomatic in the early stage and can impact gonadal function. Physicians who treat hypogonadism must be aware of the need to test cortisol levels and perform functional localization in patients with lumps present.
Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer’s disease fold
Authors: Ghosh Ujjayini , Tse Eric , Yang Hyunjun , Shi Marie , Caro Christoffer D. , Wang Feng , Merz Gregory E. , Prusiner Stanley B. , Southworth Daniel R. , Condello Carlo
Published: June 2024

Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer’s disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36–63 years of age by spectral confocal imaging with conformation-specific dyes and cryo–electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of two C-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II–like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.
Novel synthesis of some heterocycles and their molluscicidal activity against the destructive land snail, Theba pisana
Authors: Abeed Ahmed Abdou O. , El-Emary Talaat I. , Youssef Mohamed Salah K. , Hefzy Ibrahim , Ibrahim Hesham A. M.
Published: June 2024

Background

Terrestrial snails, specifically Theba pisana, represent significant agricultural pests in the Mediterranean region, particularly in Egypt. They are gastropods that cause substantial damage to a variety of vegetation, rendering them important agricultural pests that result in economic losses. In response, we have developed unique and non-toxic molluscicides. The study assessed nine novel heterocycles compared with methomyl as a reference compound, to study their molluscicidal effects on T. pisana. These heterocycles include 2-pyrazolines, 2-oxocyclohex-3-ene, and 3-cyano-2-ethoxypyridine.

Results

The obtained data revealed that the majority of the produced chemicals were remarkably effective against T. pisana snails, exhibiting different degrees of toxicity seven days post-treatment. Methomyl exhibited the highest toxicity, followed by prop-2-en-1-one and 1-thiocarbamoyl-2-pyrazoline derivatives, with LC50 values of 44.14, 59.54, and 72.00 ppm, respectively.

Conclusions

These findings will inform the potential of these synthetic compounds as one of the sources for molluscicide development and their integration into pest management strategies.

Graphical Abstract
Effect of nutrition assessment, counselling and support integration on mother-infant nutritional status, practices and health in Tororo and Butaleja districts, Uganda: A comparative non-equivalent quasi-experimental study
Authors: Namukose Samalie , Maina Gakenia Wamuyu , Kiwanuka Suzanne N , Makumbi Fredrick Edward
Published: June 2024

Background

Malnutrition remains a health challenge for women aged 15 to 49 years and their infants. While Nutrition Assessment Counselling and Support (NACS) is considered a promising strategy, evidence of its effectiveness remains scanty. This study assessed the effect of the comprehensive NACS package on the mother-infant practices, health and nutrition outcomes in two districts in Eastern Uganda.

Methods

A comparative non-equivalent quasi-experimental design was employed with two groups; Comprehensive NACS (Tororo) and Routine NACS (Butaleja). Pregnant mothers were enrolled spanning various trimesters and followed through the antenatal periods and post-delivery to monitor their health and nutrition status. Infants were followed for feeding practices, health and nutritional status at birth and weeks 6, 10, 14 and at months 6, 9 and 12 post-delivery. Propensity score matching ensured study group comparability. The NACS effect was estimated by nearest neighbour matching and the logistic regression methods. Statistical analysis utilised STATA version 15 and R version 4.1.1.

Results

A total of 666/784 (85%) with complete data were analysed (routine: 412, comprehensive: 254). Both groups were comparable by mothers’ age, Mid Upper Arm Circumference, prior antenatal visits, meal frequency, micronutrient supplementation and instances of maternal headache, depression and diarrhoea. However, differences existed in gestation age, income, family size, education and other living conditions. Comprehensive NACS infants exhibited higher infant birth weights, weight-for-age z-scores at the 3rd -6th visits (p < 0.001), length-for-age z scores at the 4th -7th visits (p < 0.001) and weight-for-length z-scores at the 3rd − 5th (p < = 0.001) visits. Despite fewer episodes of diarrhoea and fever, upper respiration infections were higher.

Conclusions

The comprehensive NACS demonstrated improved mother-infant nutritional and other health outcomes suggesting the need for integrated and holistic care for better maternal, infant and child health.
Longitudinally extensive transverse myelitis with trident sign and positive AQP4 antibody: a case report
Authors: Shojaei Maziar , Maghsudloo Faezeh , Ramezani Mahtab , Ahmadzadeh Arman , Monjazeb Somayeh , Rezaii Amir , Sahraian Mohammad Ali
Published: June 2024

Background

Longitudinally extensive transverse myelitis (LETM) is characterized by spinal cord lesions that affect at least three spinal cord segments. It can be associated with various inflammatory conditions. While imaging characteristics can aid in diagnosis, relying solely on them may lead to misinterpretation.

Case presentation

We describe a 35-year-old woman who presented with subacute myelitis. Her cervical MRI (magnetic resonance imaging) revealed an extensive lesion from the area postrema down to the second thoracic level, with a trident sign observed in axial T1-weighted post-gadolinium imaging. The presence of a trident sign in MRI of patients with myelopathy is more commonly associated with sarcoidosis than other conditions. But our patient had positive (rechecked) AQP4 antibody and negative FDG-PET (fluorodeoxyglucose positron emission tomography) scan that shows trident sign could be seen in other inflammatory disorders such as NMO (neuromyelitis optica).

Conclusion

Trident sign is not pathognomonic for sarcoidosis, additional investigations are necessary to identify the diagnoses related to the trident sign.
Unveiling the evolution of generative AI (GAI): a comprehensive and investigative analysis toward LLM models (2021–2024) and beyond
Authors: Akhtar Zarif Bin
Published: June 2024

This comprehensive exploration of recent breakthroughs in artificial intelligence (AI) traversed the realms of language models, computer vision, and generative models, unraveling the intricacies of cutting-edge technologies such as GPT-3.5, GPT-4, Pix2Seq, and multimodal models in terms of generative AI. In this multifaceted journey, the focus extended beyond technological prowess to ethical considerations, emphasizing responsible AI practices guided by Google's AI Principles. The nuanced discussions encapsulated the transformative impact of AI on user experiences across various Google products and toolsets, paving the way for a future where natural language interaction, creative content generation, and multimodal understanding redefine human–computer interactions. The research investigation showcased not only the advancements themselves but also the critical lens through which these innovations are approached, underscoring the importance of ethical and responsible AI in shaping the technological landscape.
TOP: A phase III, multicentre, randomized controlled study comparing osimertinib in combination with carboplatin and pemetrexed to osimertinib monotherapy for untreated patients with advanced non-squamous (Non-sq) non-small cell lung cancer (NSCLC) with concurrent EGFR and TP53 mutations.
Authors: Yang Yunpeng , Feng Weineng , Jiang Wei , Huang Lu , Zhao Yanqiu , Chen Lili , Fang Yong , Ji Mei , Zhang Tingting , Zhu Junfei , Zhang Li
Published: June 2024

TPS8662

Background: Osimertinib is the current standard first-line treatment for advanced non-sq NSCLC with sensitive EGFR mutations. However, previous studies demonstrated that patients with concurrent EGFR and TP53 mutations had suboptimal clinical benefit with EGFR-TKI monotherapy. FLAURA2 study showed that osimertinib plus pemetrexed and platinum-based chemotherapy significantly improved progression-free survival (PFS) compared with osimertinib monotherapy for EGFR-mutated advanced NSCLC patients. Further study is needed to better understand the benefits of the FLAURA2 model for patients with concurrent mutations. The objective of this study is to determine whether osimertinib plus chemotherapy could improve efficacy compared with osimertinib monotherapy in patients with concurrent EGFR and TP53 Mutations. Methods: This is a phase III, randomized, open-label trial in patients with advanced Non-sq NSCLC harboring EGFR mutations (exon 19 deletion or L858R) and TP53 mutations, with a performance status of 0 to 1, and planned to receive first-line therapy. Eligible patients will be randomized 1:1 to osimertinib monotherapy arm (osimertinib 80 mg orally per day) or combination therapy arm (osimertinib 80 mg orally per day plus pemetrexed 500 mg/m2 and carboplatin area under curve 5 intravenously every 3 weeks for four cycles, followed by maintenance pemetrexed and osimertinib). Randomization will be stratified by PS score (0 vs. 1), brain metastases status (yes vs. no) and mutation type (exon 19 deletion vs. L858R). The primary end point is PFS per RECIST 1.1 assessed by investigator. Secondary end points include overall survival, objective response rate, duration of response, adverse events and quality of life. Exploratory endpoint is correlation between concurrent mutations other than TP53 and efficacy, and the resistance mechanisms to combination therapy revealed by dynamic ctDNA profiling. Approximately 170 PFS events will be required to detect hazard ratio of 0.65 with 80% power at a two-sided significance level of 0.05. 292 patients will be enrolled. Until February 1, 2024, 204 patients have been enrolled, the last patient is expected to be enrolled in June 2024. Clinical trial information: NCT04695925 .
A randomized, controlled, multicenter, phase 3 study of vusolimogene oderparepvec (VO) combined with nivolumab vs treatment of physician’s choice in patients with advanced melanoma that has progressed on anti–PD-1 and anti–CTLA-4 therapy (IGNYTE-3).
Authors: Luke Jason J. , Kong George , Gullo Giuseppe , Robert Caroline
Published: June 2024

TPS9604

Background: Melanoma is the 5th most common cancer type, with ~100,000 new cases and ~8,000 deaths estimated in the US for 2024. First-line systemic treatment with immune checkpoint inhibitors improved the objective response rate (ORR) and extended progression-free survival (PFS) and overall survival (OS) for patients with advanced disease. The combination of anti–PD-1 nivolumab (nivo) + anti–CTLA-4 ipilimumab (ipi) therapy is associated with the highest ORR and best PFS and OS in this setting. However, only about half of patients respond, and there is no standard of care for patients who progress after anti–PD-1–based therapy. VO (also referred to as RP1) is a selectively replication-competent HSV-1 oncolytic virus that expresses human GM-CSF and a fusogenic glycoprotein (GALV-GP-R–). Preliminary data from the phase 1/2 study (IGNYTE) showed that intratumoral (IT) VO plus intravenous (IV) nivolumab (nivo) was well tolerated and had meaningful antitumor activity (ORR, 31.4%) with durable responses in patients with advanced melanoma who progressed on prior anti–PD-1 therapy. This phase 3 study will evaluate the overall survival and clinical benefit as well as the safety of VO plus nivo for patients with advanced melanoma whose disease has progressed after receiving anti–PD-1 and anti–CTLA-4 therapy (or who are not eligible for anti–CTLA-4 therapy in addition to anti–PD-1) versus physician’s choice. Methods: This is a randomized, controlled, multicenter, phase 3 clinical trial comparing VO in combination with nivo vs physician’s choice of treatment in patients with unresectable or metastatic melanoma. Key eligibility criteria include age ≥12 years, stage IIIb–IV/M1a–M1d cutaneous melanoma, confirmed disease progression on an anti–PD–1 and anti–CTLA-4 treatment (administered in combination or in sequence with anti–PD-1 last), at least 1 measurable tumor (≥1 cm), and adequate hematologic, hepatic, and renal function. Patients who are not candidates for anti–CTLA-4 therapy may enroll if they have confirmed progression on anti–PD-1 therapy. Patients with BRAF V600 mutant melanoma must have received an anti-BRAF + anti-MEK targeted therapy prior to enrollment. Patients (N = ~400) will be randomized 1:1 to receive VO plus nivo or physician’s choice (nivo + relatlimab, anti–PD–1 monotherapy rechallenge [nivo or pembrolizumab], or single-agent chemotherapy [dacarbazine, temozolomide, or paclitaxel/albumin-bound paclitaxel]). VO is given IT Q2W; nivo is administered IV at 240 mg Q2W or 480 mg Q4W starting with the 2nd dose of VO. The primary endpoint of the study is OS; the key secondary endpoints are PFS and ORR. Additional endpoints include complete response rate, duration of response, disease control rate, and safety. Clinical trial information: NCT06264180 .
Intralesional administration of L19IL2/L19TNF in high-risk locally advanced basal cell carcinoma or cutaneous squamous cell carcinoma.
Authors: Flatz Lukas , Leiter Ulrike M. , Meraz Torres Francisco , Wolfsperger Frederik Carlos , Meiwes Andreas , Wagner Nikolaus , Nadal Lisa , Puca Emanuele , Durak Derya , Covelli Alfredo , Elia Giuliano , Cozzio Antonio , Neri Dario , Amaral Teresa
Published: June 2024

TPS9617

Background: Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) account for 99% of skin neoplasms, with a rising incidence due to increased sun exposure and growing life expectancy. Approximately 0.8-5% of patients (pts) develop high-risk locally advanced (LA) disease, which is treated with surgery, radiotherapy, sonic hedgehog inhibitors, PD1-based immune checkpoint blockade, or chemotherapy. While surgery offers high cure rates, factors such as location, functional and cosmetic impairment, or patient factors including age, comorbidities, and personal preferences may preclude surgery. Intralesional treatment with immunostimulatory drugs represents an attractive therapeutic approach to treat LA BCC and LA cSCC. Here, we investigate a combination of two immunocytokines (Bifikafusp alfa (L19IL2) and Onfekafusp alfa (L19TNF)) targeting the extradomain B of fibronectin (EDB) for the treatment of high-risk locally advanced BCC and cSCC. EDB is an oncofetal antigen that is undetectable in virtually all healthy adult tissues but becomes highly expressed in tumors, including BCC and cSCC. Methods: In a single-arm phase II study (NCT04362722), pts with locally advanced, non-metastatic, node-negative, single, or multifocal BCC or cSCC not eligible for surgery or radiotherapy are treated with four weekly intratumoral administrations of L19IL2/L19TNF. The study is divided into two parts: a first exploratory part with a total of 40 pts with laBCC or lacSCC, and a second part where the laBCC cohort has been expanded to up to 72 pts not eligible for surgery or radiotherapy. The first part of the trial has been completed with 28 laBCC pts and 12 lacSCC pts evaluable for safety and efficacy. The pre-specified activity goal for the first stage of accrual was met, and the second stage of accrual began in September 2023, with a total of 39 BCC and 18 cSCC pts enrolled so far. Clinical trial information: NCT04362722 .
Urine Biopsy as Dynamic Biomarker to Enhance Clinical Staging of Bladder Cancer in Radical Cystectomy Candidates
Authors: Satyal Uttam , Valentine Henkel , Liu David , Slifker Michael , Lallas Costas D. , Trabulsi Edouard J. , Bukavina Laura , Szeto Lauren , Hoffman-Censits Jean H. , Mouw Kent W. , Faltas Bishoy M. , Grivas Petros , Ibragimova Ilsiya , Porten Sima P. , Van Allen Eliezer M. , Geynisman Daniel M. , Parker Daniel C. , O'Neill John P. , Drevik Johnathan , Christianson Sarah S. , Ginzburg Serge , Correa Andres F. , Uzzo Robert G. , Ross Eric A. , Zibelman Matthew R. , Ghatalia Pooja , Plimack Elizabeth R. , Kutikov Alexander , Abbosh Philip H.
Published: June 2024

PURPOSE

There is significant interest in identifying complete responders to neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) to potentially avoid removal of a pathologically benign bladder. However, clinical restaging after NAC is highly inaccurate. The objective of this study was to develop a next-generation sequencing–based molecular assay using urine to enhance clinical staging of patients with bladder cancer.

METHODS

Urine samples from 20 and 44 patients with bladder cancer undergoing RC were prospectively collected for retrospective analysis for molecular correlate analysis from two clinical trials, respectively. The first cohort was used to benchmark the assay, and the second was used to determine the performance characteristics of the test as it correlates to responder status as measured by pathologic examination.

RESULTS

First, to benchmark the assay, known mutations identified in the tissue (MT) of patients from the Accelerated Methotrexate, Vinblastine, Doxorubicin, Cisplatin trial (ClinicalTrials.gov identifier: NCT01611662 , n = 16) and a cohort from University of California-San Francisco (n = 4) were cross referenced against mutation profiles from urine (MU). We then determined the correlation between MU persistence and residual disease in pre-RC urine samples from a second prospective clinical trial (The pT0 trial; ClinicalTrials.gov identifier: NCT02968732 ). Residual MU status correlated strongly with residual disease status (pT0 trial; n = 44; P = .0092) when MU from urine supernatant and urine pellet were assessed separately and analyzed in tandem. The sensitivity, specificity, PPV, and NPV were 91%, 50%, 86%, and 63% respectively, with an overall accuracy of 82% for this second cohort.

CONCLUSION

MU are representative of MT and thus can be used to enhance clinical staging of urothelial carcinoma. Urine biopsy may be used as a reliable tool that can be further developed to identify complete response to NAC in anticipation of safe RC avoidance.
Synthetic Lethality Beyond BRCA: A Phase I Study of Rucaparib and Irinotecan in Metastatic Solid Tumors With Homologous Recombination-Deficiency Mutations Beyond BRCA1/2
Authors: Tsang Erica S. , Dhawan Mallika S. , Pacaud Romain , Thomas Scott , Grabowsky Jennifer , Wilch Lauren , Karipineni Silpa , Kelley Robin Kate , Ko Andrew H. , Collisson Eric , Chapman Jocelyn S. , Ueda Stefanie , Bergsland Emily K. , Munster Pamela
Published: June 2024

PURPOSE

Combining poly ADP-ribose polymerase (PARP) and topoisomerase I inhibitors has demonstrated synergistic effects in in vivo models. This phase I trial evaluated rucaparib and irinotecan in metastatic solid tumors with homologous recombination deficiency.

METHODS

This study enrolled patients in three cohorts to determine the tolerability and preliminary efficacy of (1) rucaparib 400 mg PO twice a day (days 1-7, 15-21) and irinotecan 65 mg/m2 intravenously once every 2 weeks; (2) rucaparib 400 mg PO twice a day (D1-7, 15-21) and irinotecan 100 mg/m2 once every 2 weeks; and (3) rucaparib 400 mg per os twice a day (D1-7) and irinotecan 100 mg/m2 once every 3 weeks.

RESULTS

Twenty patients were enrolled: 95% with previous platinum, 40% with previous irinotecan, and 20% with previous PARP inhibitor. The maximally tolerated was determined as rucaparib 400 mg twice a day days 1-7 and irinotecan 100 mg/m2 once every 3 weeks. Four dose-limiting toxicities (all grade 3-4 neutropenia) occurred during dose escalation with only neutropenia as other grade 3-4 toxicities (25%; grade 3 [n = 3], grade 4 [n = 2]). Treatment-related grade 1-2 adverse events included neutropenia (45%), diarrhea (45%), nausea (40%), and fatigue (30%). Of 17 patients with evaluable disease, six patients (35%) derived clinical benefit (n = 2 with PR, n = 4 with stable disease for over 6 months). Three patients remained on study >1 year: two with ATM mutations (small bowel carcinoma and pancreatic neuroendocrine tumor) and one patient with a PALB2 mutation (primary peritoneal cancer).

CONCLUSION

Pulse dosing of rucaparib and once every 3 weeks irinotecan was well tolerated for up to 18 months with durable responses in BRCA-, PALB2-, and ATM-mutated cancers despite progression on previous platinum.