Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple-negative breast cancer: a phase 2 adaptive trial.

Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II-III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8+ T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8+ T cells, follicular helper T cells and shorter distances between tumor and CD8+ T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon's two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890 .

In situ structure and rotary states of mitochondrial ATP synthase in whole Polytomella cells.

Cells depend on a continuous supply of adenosine triphosphate (ATP), the universal energy currency. In mitochondria, ATP is produced by a series of redox reactions, whereby an electrochemical gradient is established across the inner mitochondrial membrane. The ATP synthase harnesses the energy of the gradient to generate ATP from adenosine diphosphate (ADP) and inorganic phosphate. We determined the structure of ATP synthase within mitochondria of the unicellular flagellate Polytomella by electron cryo-tomography and subtomogram averaging at up to 4.2-angstrom resolution, revealing six rotary positions of the central stalk, subclassified into 21 substates of the F1 head. The Polytomella ATP synthase forms helical arrays with multiple adjacent rows defining the cristae ridges. The structure of ATP synthase under native operating conditions in the presence of a membrane potential represents a pivotal step toward the analysis of membrane protein complexes in situ.

Genetic Implications and Management of Epidermolysis Bullosa in the Saudi Arabian Population.

Epidermolysis bullosa (EB) is a genetic skin disorder characterized by skin fragility and blister formation. This review explores the genetic basis and management of EB in the Saudi population, emphasizing the need for genetic insights to enable precise diagnosis, targeted treatments, and effective counseling. Diagnosis in Saudi Arabia relies on clinical assessments and genetic testing. Prenatal diagnosis may be suggested in families with children affected by EB, but it is not widely used in the Middle East. Current management focuses on symptom relief, while emerging experimental approaches such as gene and stem cell therapies are under extensive research. Challenges in EB research include developing effective targeted therapies and understanding the variability in how genotypes manifest phenotypically. Continuous research is crucial to enhance diagnostic methods, therapeutic approaches, and overall patient care.

The immunomicrotope of Leishmania control and persistence.

Leishmania is an intracellular protozoan transmitted by sand fly vectors; it causes cutaneous, mucocutaneous, or visceral disease. Its growth and survival are impeded by type 1 T helper cell responses, which entail interferon (IFN)-γ-mediated macrophage activation. Leishmania partially escapes this host defense by triggering immune cell and cytokine responses that favor parasite replication rather than killing. Novel methods for in situ analyses have revealed that the pathways of immune control and microbial evasion are strongly influenced by the tissue context, the micro milieu factors, and the metabolism at the site of infection, which we collectively term the 'immunomicrotope'. Understanding the components and the impact of the immunomicrotope will enable the development of novel strategies for the treatment of chronic leishmaniasis.

Cytotoxicity by endocrine disruptors through effects on ER Ca2+ transporters, aberrations in Ca2+ signalling pathways and ER stress.

Concerns regarding man-made organic chemicals pervading our ecosystem and having adverse and detrimental effects upon organisms, including man, have now been studied for several decades. Since the 1970s, some environmental pollutants were identified as having endocrine disrupting affects. These endocrine disrupting chemicals (EDC) were initially shown to have estrogenic or anti-estrogenic properties and some were also shown to bind to a variety of hormone receptors. However, since the 1990s it has also been identified that many of these EDC additionally, have the ability of causing abnormal alterations in Ca2+ signalling pathways (also commonly involved in hormone signalling), leading to exaggerated elevations in cytosolic [Ca2+] levels, that is known to cause activation of a number of cell death pathways. The major emphasis of this review is to present a personal perspective of the evidence for some types of EDC, specifically alkylphenols and brominated flame retardants (BFRs), causing direct effects on Ca2+ transporters (mainly the SERCA Ca2+ ATPases), culminating in acute cytotoxicity and cell death. Evidence is also presented to indicate that this Ca2+ATPase inhibition, which leads to abnormally elevated cytosolic [Ca2+], as well as a decreased luminal ER [Ca2+], which triggers the ER stress response, are both involved in acute cytotoxicity.

The Role of Screening, Risk Factors, and Early Intervention in Preventing Diabetes in the Obese Population: A Systematic Review.

With its rising global prevalence, diabetes has become one of the most significant and challenging health problems afflicting the world's population today. The increasing burden of diabetes and its associated complications calls for immediate action for prevention which primarily includes addressing the risk factors. The most significant risk factor for the onset of diabetes is obesity. Obesity and diabetes rates have been rising simultaneously, posing a threat to patient mortality and driving up community healthcare costs. A weight loss of five percent or more of total body weight has been shown to improve the quality of life, reduce the need for pharmacological therapy for diabetes, and enhance glycemic control. This level of weight loss can have significant health benefits, particularly for individuals with diabetes or at risk for developing diabetes. We aim to conduct this systematic review to assess diverse risk factors contributing to the incidence of diabetes among the obese population and determine various preventive strategies and recommendations in practice for the prevention of diabetes in this cohort. As a result, we included original studies that recruited the obese and diabetic populations and defined preventive measures for early intervention. Additionally, we included studies published in the last 10 years (2014-2024) only for the latest evidence. Studies including obese populations with cardiovascular diseases and neurological disorders were excluded. The Newcastle-Ottoman Castle assessment tool was utilized to assess the quality of the studies. We included nine studies that recruited 60,645 patients and were published between 2015 and 2022. Findings suggest that obesity alone is a significant contributor to the occurrence or onset of diabetes. At the same time, the presence of other risk factors, including hypertension, dyslipidemia, elevated triglycerides, or HDL and LDL levels, may further increase the risk of diabetes and its associated complications among the obese population. Preventive strategies emphasize early intervention through increasing awareness and educating communities about risk factors and lifestyle interventions, including the limitations of fast food diets for the prevention of diabetes and weight control. Since obesity is considered to be an independent risk factor for the development of diabetes, addressing and managing it is of critical importance clinically. Targeted early interventions, including screening for risk factors, health promotion, and education activities, can aid in the adaptation of healthier lifestyles, which can reduce the burden of these diseases significantly.

Approach in inputs & outputs selection of Data Envelopment Analysis (DEA) efficiency measurement in hospitals: A systematic review.

The efficiency and productivity evaluation process commonly employs Data Envelopment Analysis (DEA) as a performance tool in numerous fields, such as the healthcare industry (hospitals). Therefore, this review examined various hospital-based DEA articles involving input and output variable selection approaches and the recent DEA developments. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was utilised to extract 89 English articles containing empirical data between 2014 and 2022 from various databases (Web of Science, Scopus, PubMed, ScienceDirect, Springer Link, and Google Scholar). Furthermore, the DEA model parameters were determined using information from previous studies, while the approaches were identified narratively. This review grouped the approaches into four sections: literature review, data availability, systematic method, and expert judgement. An independent single strategy or a combination with other methods was then applied to these approaches. Consequently, the focus of this review on various methodologies employed in hospitals could limit its findings. Alternative approaches or techniques could be utilised to determine the input and output variables for a DEA analysis in a distinct area or based on different perspectives. The DEA application trend was also significantly similar to that of previous studies. Meanwhile, insufficient data was observed to support the usability of any DEA model in terms of fitting all model parameters. Therefore, several recommendations and methodological principles for DEA were proposed after analysing the existing literature.

Gene expression profile of immune-check point in response to Trastuzumab therapy in patients with HER-2 positive breast cancer.

OBJECTIVE: Aim: To clarify the association between response to Trastuzumab and molecular expression of TIM-3 and FOXP-3 immune checkpoints. PATIENTS AND METHODS: Materials and Methods: FOXP-3 and TIM-3 expression in peripheral blood was analyzed using qPCR, and the serum level of Trastuzumab was estimated using an immune sorbent enzyme assay. RESULTS: Results: During treatment with Trastuzumab, the FOXP-3 gene expression showed a significant decline throughout one year of treatment, going from 0.85 at cycle 9 to 0.75 at cycle 17. While the TIM-3 gene expression showed a significant up regulation at cycle 9 to 2.8 fold, followed by a reduction in the fold change from 2.8 to 1.7 in the font of reference gene expression. CONCLUSION: Conclusions:FOXP-3 and TIM-3 have the potential to be suggestive markers that can anticipate the response to Trastuzumab, but they are not capable of predicting the likelihood of recurrence.

MLIP and Its Potential Influence on Key Oncogenic Pathways.

Muscle-enriched A-type lamin-interacting protein (MLIP) is an emerging protein involved in cellular homeostasis and stress adaptation. Eukaryotic cells regulate various cellular processes, including metabolism, DNA repair, and cell cycle progression, to maintain cellular homeostasis. Disruptions in this homeostasis can lead to diseases such as cancer, characterized by uncontrolled cell growth and division. This review aims to explore for the first time the unique role MLIP may play in cancer development and progression, given its interactions with the PI3K/Akt/mTOR pathway, p53, MAPK9, and FOXO transcription factors, all critical regulators of cellular homeostasis and tumor suppression. We discuss the current understanding of MLIP's involvement in pro-survival pathways and its potential implications in cancer cells' metabolic remodeling and dysregulated homeostasis. Additionally, we examine the potential of MLIP as a novel therapeutic target for cancer treatment. This review aims to shed light on MLIP's potential impact on cancer biology and contribute to developing innovative therapeutic strategies.

Unveiling G-protein coupled receptors as potential targets for ovarian cancer nanomedicines: from RNA sequencing data analysis to in vitro validation.

Genetic heterogeneity in ovarian cancer indicates the need for personalised treatment approaches. Currently, very few G-protein coupled receptors (GPCRs) have been investigated for active targeting with nanomedicines such as antibody-conjugated drugs and drug-loaded nanoparticles, highlighting a neglected potential to develop personalised treatment. To address the genetic heterogeneity of ovarian cancer, a future personalised approach could include the identification of unique GPCRs expressed in cancer biopsies, matched with personalised GPCR-targeted nanomedicines, for the delivery of lethal drugs to tumour tissue before, during and after surgery. Here we report on the systematic analysis of public ribonucleic acid-sequencing (RNA-seq) gene expression data, which led to prioritisation of 13 GPCRs as candidates with frequent overexpression in ovarian cancer tissues. Subsequently, primary ovarian cancer cells derived from ascites and ovarian cancer cell lines were used to confirm frequent gene expression for the selected GPCRs. However, the expression levels showed high variability within our selection of samples, therefore, supporting and emphasising the need for the future development of case-to-case personalised targeting approaches.

Garlic bioactive substances and their therapeutic applications for improving human health: a comprehensive review.

Garlic (Allium sativum L.) is a widely abundant spice, known for its aroma and pungent flavor. It contains several bioactive compounds and offers a wide range of health benefits to humans, including those pertaining to nutrition, physiology, and medicine. Therefore, garlic is considered as one of the most effective disease-preventive diets. Many in vitro and in vivo studies have reported the sulfur-containing compounds, allicin and ajoene, for their effective anticancer, anti-diabetic, anti-inflammatory, antioxidant, antimicrobial, immune-boosting, and cardioprotective properties. As a rich natural source of bioactive compounds, including polysaccharides, saponins, tannins, linalool, geraniol, phellandrene, ß-phellandrene, ajoene, alliin, S-allyl-mercapto cysteine, and ß-phellandrene, garlic has many therapeutic applications and may play a role in drug development against various human diseases. In the current review, garlic and its major bioactive components along with their biological function and mechanisms of action for their role in disease prevention and therapy are discussed.

Anticoagulation Versus Antiplatelets in Spontaneous Cervical Artery Dissection: A Systematic Review and Meta-Analysis.

BACKGROUND: It is uncertain whether antiplatelets or anticoagulants are more effective in preventing early recurrent stroke in patients with cervical artery dissection. Following the publication of the observational Antithrombotic for STOP-CAD (Stroke Prevention in Cervical Artery Dissection) study, which has more than doubled available data, we performed an updated systematic review and meta-analysis comparing antiplatelets versus anticoagulation in cervical artery dissection. METHODS: The systematic review was registered in PROSPERO (CRD42023468063). We searched 5 databases using a combination of keywords that encompass different antiplatelets and anticoagulants, as well as cervical artery dissection. We included relevant randomized trials and included observational studies of dissection unrelated to major trauma. Where studies were sufficiently similar, we performed meta-analyses for efficacy (ischemic stroke) and safety (major hemorrhage, symptomatic intracranial hemorrhage, and death) outcomes using relative risks. RESULTS: We identified 11 studies (2 randomized trials and 9 observational studies) that met the inclusion criteria. These included 5039 patients (30% [1512] treated with anticoagulation and 70% [3527]) treated with antiplatelets]. In meta-analysis, anticoagulation was associated with a lower ischemic stroke risk (relative risk, 0.63 [95% CI, 0.43 to 0.94]; P=0.02; I2=0%) but higher major bleeding risk (relative risk, 2.25 [95% CI, 1.07 to 4.72]; P=0.03, I2=0%). The risks of death and symptomatic intracranial hemorrhage were similar between the 2 treatments. Effect sizes were larger in randomized trials. There are insufficient data on the efficacy and safety of dual antiplatelet therapy or direct oral anticoagulants. CONCLUSIONS: In this study of patients with cervical artery dissection, anticoagulation was superior to antiplatelet therapy in reducing ischemic stroke but carried a higher major bleeding risk. This argues for an individualized therapeutic approach incorporating the net clinical benefit of ischemic stroke reduction and bleeding risks. Large randomized clinical trials are required to clarify optimal antithrombotic strategies for management of cervical artery dissection.

Tilting and Distortion in the Multiferroic Aurivillius Phase Bi6Ti3Fe1.5Mn0.5O18.

Aurivillius structured Bi6Ti3Fe1.5Mn0.5O18 (B6TFMO) has emerged as a rare room temperature multiferroic, exhibiting reversible magnetoelectric switching of ferroelectric domains under cycled magnetic fields. This layered oxide presents exceptional avenues for advancing data storage technologies owing to its distinctive ferroelectric and ferrimagnetic characteristics. Despite its immense potential, a comprehensive understanding of the underlying mechanisms driving multiferroic behavior remains elusive. Herein, we employ atomic resolution electron microscopy to elucidate the interplay of octahedral tilting and atomic-level structural distortions within B6TFMO, associating these phenomena with functional properties. Fundamental electronic features at varying bonding environments within this complex system are scrutinized using electron energy loss spectroscopy (EELS), revealing that the electronic nature of the Ti4+ cations within perovskite BO6 octahedra is influenced by position within the Aurivillius structure. Layer-by-layer EELS analysis shows an ascending crystal field splitting (Δ) trend from outer to center perovskite layers, with an average increase in Δ of 0.13 ± 0.06 eV. Density functional theory calculations, supported by atomic resolution polarization vector mapping of B-site cations, underscore the correlation between the evolving nature of Ti4+ cations, the extent of tetragonal distortion and ferroelectric behavior. Integrated differential phase contrast imaging unveils the position of light oxygen atoms in B6TFMO for the first time, exposing an escalating degree of octahedral tilting toward the center layers, which competes with the magnitude of BO6 tetragonal distortion. The observed octahedral tilting, influenced by B-site cation arrangement, is deemed crucial for juxtaposing magnetic cations and establishing long-range ferrimagnetic order in multiferroic B6TFMO.

Assessing the correlation between the degree of tricuspid regurgitation and pulmonary hypertension: A comprehensive study.

OBJECTIVES: To evaluate the relationship between severity of tricuspid regurgitation (TR) and pulmonary hypertension. METHODS: Cross-sectional study of 118 patients with pulmonary hypertension was carried out at a single center in Jeddah, Saudi Arabia, between 2018-2021. Patients who had pulmonary or tricuspid valves organic diseases, previously undergone tricuspid or pulmonary valve surgeries, had permanent pacemakers or critically ill were excluded. RESULTS: A high proportion of patients were women (n=100, 85%) and obese (n=57, 48%). Patients with more than mild TR had higher systolic pulmonary artery pressure (sPAP) than those with trivial or mild regurgitation (p<0.001). There was a significant association between severity of TR (p<0.001) and right chambers size (p=0.001). Furthermore, pulmonary artery pressure (PAP) was significantly higher in patients with mild right ventricular impairment (p=0.001). CONCLUSION: Increase in degree of TR and right atrial size were predictors of elevated sPAP. Our findings highlight the interplay among TR, right heart size, ventricular function, and PAP. Understanding these associations can aid in risk stratification, monitoring disease progression, and potentially guiding treatment in those patients.

Melatonin mitigates cisplatin-induced cognitive impairment in rats and improves hippocampal dendritic spine density.

Cisplatin-induced cognitive impairment (chemobrain) affects a considerable percentage of cancer patients and has no established pharmacological treatment. Chemobrain can be associated with neuroinflammation and oxidative stress. Melatonin, a pineal hormone, is known to have antioxidant, anti-inflammatory and neuroprotective potential. In this study, we investigated cisplatin-induced cognitive impairment in rats and whether melatonin can improve or reverse this impairment. Behavioral testing involved measuring working memory using the novel location recognition test (NLRT) under conditions of cisplatin or cisplatin + melatonin treatment, followed by the collection of rats' brains. The brains were subsequently stained with Golgi-Cox stain and then the hippocampus area CA3 of each one was examined, and dendritic spine density was calculated. Treatment with cisplatin resulted in deficits in the rats' performance in the NLRT (P < 0.05). These deficits were prevented by the coadministration of melatonin (P < 0.05). Cisplatin also reduced the density of dendritic spines in the hippocampus (P < 0.0001), specifically CA3 area, while the coadministration of melatonin significantly reversed this reduction (P < 0.001). This study showed that melatonin can ameliorate cisplatin-induced spatial memory deficits and dendritic spines density abnormalities in rats. Given that melatonin is a safe and wildly used supplement, it is feasible to explore its use as a palliative intervention in cancer treatment.

Sulforaphane protects against LPS-induced liver injury in mice by antagonizing oxidative stress and apoptosis through AMPK activation.

Objectives: Given the adverse effect of liver injury on a multitude of body functions, it is vital to understand its underlying mechanism and how to overcome it. In this study, lipopolysaccharide (LPS) was used to induce liver injury, while sulforaphane (SFN), a natural phytochemical, was used as the antagonist to overcome the deleterious effect. Methods: Twenty-four mice were divided into three groups: Control group (0.9% saline), LPS induction group (0.75 mg/kg), and SFN treatment (25 mg/kg) followed by LPS induction group (0.75 mg/kg), all with access to food and water ad libitum. Blood samples from retro-orbital sinus were used to measure liver function through two aminotransferases (i.e., alanine transaminase [ALT] and aspartate transaminase [AST]) whereas liver homogenate was used to measure glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) (antioxidant activity markers); caspase-3 (apoptosis marker); malondialdehyde (MDA) (lipid peroxidation marker); and NO. AMP-activated protein kinase (AMPK), a cellular energy homeostasis and lipid metabolism sensor, was also measured. Statistical analysis including normalization, analysis of variance, Kruskal-Wallis test, and significance of P < 0.05 were applied to all collected data. Results: SFN treatment significantly attenuated all tests compared to the induced liver injury by LPS where significant reduction was observed in the levels of hepatic function markers (AST and ALT), lipid peroxidation marker (MDA) as well as apoptosis marker (caspase-3) whereas a marked increase was observed for antioxidant activity markers (SOD, CAT, and GSH) and AMPK. Conclusion: These results indicate the protective effect of SFN as it re-instated the levels of antioxidation while decreasing the level of the biomarkers, which were significantly increased during liver injury induction by LPS.

Engineered CAR-T cells targeting the non-functional P2X purinoceptor 7 (P2X7) receptor as a novel treatment for ovarian cancer.

Objectives: Recent studies have identified expression of the non-functional P2X7 (nfP2X7) receptor on various malignant cells including ovarian cancer, but not on normal cells, which makes it a promising tumour-associated antigen candidate for chimeric antigen receptor (CAR)-T-cell immunotherapies. In this study, we assessed the cytotoxic effects of nfP2X7-CAR-T cells on ovarian cancer using in vitro and in vivo models. Methods: We evaluated the effects of nfP2X7-CAR-T cells on ovarian cancer cell lines (SKOV-3, OVCAR3, OVCAR5), normal peritoneal cells (LP-9) and primary serous ovarian cancer cells derived from patient ascites in vitro using monolayer and 3D spheroid assays. We also evaluated the effects of nfP2X7-CAR-T cells on patient-derived tissue explants, which recapitulate an intact tumour microenvironment. In addition, we investigated the effect of nfP2X7-CAR-T cells in vivo using the OVCAR-3 xenograft model in NOD-scid IL2Rγnull (NSG) mice. Results: Our study found that nfP2X7-CAR-T cells were cytotoxic and significantly inhibited survival of OVCAR3, OVCAR5 and primary serous ovarian cancer cells compared with un-transduced CD3+ T cells in vitro. However, no significant effects of nfP2X7-CAR-T cells were observed for SKOV3 or normal peritoneal cells (LP-9) cells with low P2X7 receptor expression. Treatment with nfP2X7-CAR-T cells increased apoptosis compared with un-transduced T cells in patient-derived explants and correlated with CD3 positivity. Treatment with nfP2X7-CAR-T cells significantly reduced OVCAR3 tumour burden in mice compared with un-transduced CD3 cells for 7-8 weeks. Conclusion: This study demonstrates that nfP2X7-CAR-T cells have great potential to be developed as a novel immunotherapy for ovarian cancer.