Advanced Stage Research Articles

Association of Quality of Life and Visual Function in Glaucoma with Tests of Structure and Function.

In addition to standard automated perimetry tests, contrast sensitivity testing and macular analyses may predict changes in the quality of life in patients at different stages of glaucoma. To examine the relationship between functional and structural tests of visual function and the 25-item National Eye Institute-Visual Function Questionnaire (NEI-VFQ-25) and the 36-item Short Form Health Survey (SF-36) in patients with different stages of glaucoma. Standard automated perimetry tests, optical coherence tomography scans, and contrast sensitivity (CS) testing were prospectively performed in 160 patients with glaucoma. The Hoddap-Parrish-Anderson staging system was used for glaucoma staging. Health-related quality of life questionnaires (NEI-VFQ-25, SF-36) were also administered to all patients. The study group comprised 29 patients with suspected glaucoma, 104 with mild glaucoma, 15 with moderate glaucoma, and 12 with severe glaucoma. The mean total score of the NEI-VFQ-25 was 88.8±8.2. The SF-36 did not show a significant correlation with the data on functional and structural tests of visual function, whereas the NEI-VFQ-25 showed a low to moderate correlation (r=0.212--0.492). Vision parameters can explain up to 18.6% of the total score of the NEI-VFQ-25. CS was the only function significantly correlated with glaucoma suspects, while in the early stages, VA was the strongest correlated function with the NEI-VFQ-25 total score (P=0.003 and r=0.551; P=0.001 and r=0.343, respectively). The impact of the visual field on vision-related quality of life increased in the advanced stages (P=0.013, r=0.688). The macular retinal ganglion cell plus inner plexiform layer thickness remained associated with NEI-VFQ-25 at all stages of glaucoma (r=0.335-0.802). The NEI-VFQ-25 total score and most of the subscales were correlated with the physical and mental component summary scores of the SF-36 (r=0.159-0.587). VA correlated the most with quality of life in glaucoma patients, as measured with the NEI-VFQ-25 to assess quality of life in glaucoma. The impact of visual functions on quality of life varies at different stages of glaucoma.

Machine Learning Approaches for Automated Diagnosis of Cardiovascular Diseases: A Review of Electrocardiogram Data Applications.

Cardiovascular diseases (CVDs) have been identified as the leading cause of mortality worldwide. Electrocardiogram (ECG) is a fundamental diagnostic tool used for the diagnosis and detection of these diseases. The new technological tools can help enhance the effectiveness of ECGs. Machine learning (ML) is widely acknowledged as a highly effective approach in the realm of computer-aided diagnostics. This article presents a review of the effectiveness of ML algorithms and deep-learning algorithms in diagnosing, identifying, and classifying CVDs using ECG data. The review identified relevant studies published in the 5 major databases: PubMed, Web of Science (WoS), Scopus, Springer, and IEEE Xplore; between 2021 and 2023, a total of 30 were chosen for the comprehensive quantitative and qualitative. The study demonstrated that different datasets are available online with data related to CVDs. The various ML techniques are employed for the purpose of classification. Based on our investigation, it has been observed that deep learning-based neural network algorithms, such as convolutional neural networks and deep neural networks, have demonstrated superior performance in the detection of entire record data. Furthermore, deep learning showcases its efficacy even when confronted with a scarcity of data. ML approaches utilizing ECG data exhibit a notable proficiency in the realm of diagnosis, hence holding the potential to mitigate the occurrence of disease-related consequences at advanced stages.

RAC1 serves as a prognostic factor and correlated with immune infiltration in liver hepatocellular carcinoma

BackgroundHepatocellular carcinoma (LIHC) has severe consequences due to late diagnosis and the lack of effective therapies. Currently, potential biomarkers for the diagnosis and prognosis of LIHC have not been systematically evaluated. Previous studies have reported that RAC1 is associated with the B cell receptor signaling pathway in various tumor microenvironments, but its relationship with LIHC remains unclear. We investigated the relationship between RAC1 and the prognosis and immune infiltration microenvironment of LIHC, exploring its potential as a prognostic biomarker for this type of cancer.MethodsIn this study, we analyzed data from The Cancer Genome Atlas (TCGA) using the Wilcoxon signed-rank test and logistic regression to assess the association between RAC1 expression and clinical characteristics in LIHC patients. Additionally, Kaplan-Meier and Cox regression methods were employed to confirm the impact of RAC1 expression levels on overall survival. Immunohistochemistry was used to validate RAC1 protein expression in LIHC. We constructed RAC1 knockdown LIHC cells and studied the effects of RAC1 protein on cell proliferation and migration at both cellular and animal levels.ResultsRAC1 expression levels were significantly elevated in LIHC tissues compared to normal tissues. High RAC1 expression was strongly associated with advanced pathological stages and was identified as an independent factor negatively affecting overall survival. At both cellular and animal levels, RAC1 knockdown significantly inhibited the proliferation and migration of LIHC cells. Furthermore, RAC1 expression was positively correlated with the infiltration of Th2 cells and macrophages in the tumor microenvironment, suggesting that RAC1 may contribute to the deterioration of the tumor immunosuppressive microenvironment and potentially lead to reduced patient survival.ConclusionThese findings indicate that RAC1 expression promotes LIHC proliferation and migration and influences the landscape of immune cell infiltration in the tumor microenvironment. Based on these results, RAC1 is proposed as a potential prognostic biomarker for LIHC, associated with both cancer progression and tumor immune cell infiltration.

Dysregulation of a novel m6A regulator YWHAG is correlated with metastasis and poor prognosis in oral squamous cell carcinoma – A cross-sectional study

ObjectiveThis study aimed to investigate the role of a novel m6A and cell cycle regulator YWHAG in oral squamous cell carcinoma (OSCC) by analyzing its expression and functional implications. DesignTumor samples (n = 51) and adjacent non-tumor samples (n = 38) were collected from patients with OSCC, and cell lines were processed. YWHAG mRNA expression was assessed using quantitative reverse transcription PCR (RT-qPCR) analysis. Various tools, such as UALCAN, Protein-Atlas analysis, TIMER 2.0, and other in silico tools, were used to explore clinicopathological correlations, protein expression, immune cell infiltration, and functional associations of YWHAG. ResultsYWHAG mRNA and protein expression were significantly upregulated in OSCC tumor tissues and OSCC cell lines compared to non-tumor tissues and normal cells (p < 0.001). High YWHAG expression significantly correlated with advanced tumor stage, higher grade, lymph node metastasis, and poor prognosis (p < 0.05). Functional analysis revealed that YWHAG is associated with pathways involved in aggressive cancer progression. YWHAG expression positively correlated with its target gene CTTN expression, which was also upregulated in OSCC and associated with poor prognosis (p < 0.05). ConclusionsStudy findings indicate that YWHAG may contribute to the progression of OSCC and could be a potential therapeutic target or prognostic biomarker. Further investigation is necessary to understand the underlying mechanisms and assess the clinical implications of YWHAG dysregulation in OSCC.

Clinico-Pathological Characteristics of Endometrial Carcinoma with Mismatch Repair Deficiency

Background: Endometrial carcinoma (EC) is a common gynecologic malignancy with significant implications for women's health. Mismatch repair deficiency (MMRd) has emerged as a critical factor influencing the pathogenesis and prognosis of EC. This study aims to investigate the clinicopathologic characteristics of MMRd EC in a Bangladeshi cohort. Methods: This cross-sectional observational study was conducted at the Department of Gynecological Oncology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, from March 2022 to February 2023. A total of 49 patients with histologically confirmed EC were included. Data were collected through a semi-structured questionnaire and patient records. Results: Among the 49 patients, 67.35% (n=33) were MMR proficient, while 32.65% (n=16) were MMR deficient. The mean age was 55 years for MMR proficient and 55.6 years for MMR deficient patients. Hypertension was present in 69.70% of MMR proficient and 75% of MMR deficient patients, while diabetes mellitus affected 54.55% of MMR proficient and 62.50% of MMR deficient patients. MMRd patients showed higher rates of adnexal involvement (37.50% vs. 6.06%, p=0.010) and metastasis (37.50% vs. 9.09%, p=0.024). Multivariate logistic regression identified advanced FIGO stage (III &amp; IV) as a significant predictor of MMR deficiency (adjusted OR 4.274, 95% CI: 1.691-15.515, p=0.025). Conclusion: MMRd in endometrial carcinoma is associated with more aggressive tumor features and poorer prognostic indicators. Routine evaluation of MMR status is crucial for effective prognosis and treatment planning. Addressing socioeconomic disparities and integrating targeted therapeutic strategies can improve management and outcomes for patients with MMRd endometrial carcinoma in diverse populations.

Identification of zinc finger MIZ-type containing 2 as an oncoprotein enhancing NAD-dependent protein deacetylase sirtuin-1 deacetylase activity to regulate Wnt and Hippo pathways in non-small-cell lung cancer

BackgroundZinc finger MIZ-type containing 2 (ZMIZ2) can function as a coactivator and participate in the progression of certain malignant tumors; however, its expression and underlying molecular mechanism in non-small-cell lung cancer (NSCLC) remains unknown. In this study, we aim to analyze the expression of ZMIZ2 and its tumorigenic function in NSCLC, identifying its related factors.MethodsZMIZ2 expression in NSCLC tissue samples and cell lines was examined using immunohistochemistry and western blotting; its biological role was investigated using in vivo and in vitro assays. The association between ZMIZ2 and NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was demonstrated using mass spectrometry and immunoprecipitation experiments. Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG)-based enrichment analysis, luciferase reporter assay, and real-time quantitative polymerase chain reaction (RT–qPCR) were conducted to verify the impact of ZMIZ2–SIRT1 combination on Hippo/Wnt pathways.ResultsZMIZ2 was highly expressed in NSCLC and positively associated with advanced pTNM staging, lymph node metastasis, and poor overall survival. Functional experiments revealed that ZMIZ2 promotes the proliferation, migration, and invasiveness of lung cancer cells—establishing its role as a promoter of oncogenes. Molecular mechanism studies identified SIRT1 as an assisted key factor interacting with ZMIZ2. KEGG enrichment analysis revealed that ZMIZ2 is closely related to Wnt/Hippo pathways; ZMIZ2–SIRT1 interaction enhanced SIRT1 deacetylase activity. Direct downregulation of intranuclear β-catenin and yes-associated protein (YAP) acetylation levels occurred independently of upstream proteins in Wnt/Hippo pathways; transcriptional activities of β-catenin-transcription factor 4 (TCF4) and YAP–TEA domain family transcription factors (TEADs) were amplified.ConclusionsZMIZ2 promotes the malignant phenotype of lung cancer by regulating Wnt/Hippo pathways through SIRT1, providing an experimental basis for discovering novel biomarkers and developing tumor-targeted drugs.Graphical

Second opinion and self-efficacy in German skin cancer patients.

The global incidence of skin cancer has steadily increased in recent years. Accordingly, patients require information on diagnosis and treatment options while dealing with the perceived impact of the diagnosis. In 2015, the German government enacted legislation under the Social Code (SGBV, §27b), granting patients the right to obtain a second medical opinion. Utilizing a standardized questionnaire, our study aims to explore whether patients diagnosed with skin cancer actively pursue a second medical opinion and to evaluate any potential disruptions to their daily lives. We collected a total of 714 completed questionnaires. The majority of those seeking a second opinion were diagnosed with malignant melanoma (96, 58%). Primary motivations for seeking a second opinion included seeking reassurance regarding treatment decisions and obtaining further information. Additionally, seeking a second opinion was correlated with a significantly lower internal locus of control, indicating a belief that their actions are not solely determined by their own abilities. Notably, we observed a greater impairment of daily life among younger participants and those with advanced cancer. Overall, our study shows that second opinions often strengthened the patient-physician interaction and provided additional reassurance, especially in patients with a weak perception of control. Moreover, we found that the impairment of quality of life and both internal and external locus of control decrease significantly in advanced tumor stages. Hence, it is imperative to identify additional interventions aimed at bolstering internal resilience and locus of control, thereby enhancing patients' capacity to cope with their cancer diagnosis.

Social relations among older gay men and trans women in Chile: Diverse, intimate, functional and reciprocal networks

Although LGTBIQ+ groups have experienced social transformations towards greater levels of respect and public presence in Chile in recent decades, the life trajectories of older people remain marginal in studies and surveys regarding sexual and gender diversity. In a society where homophobia is a current and oppressive attitude despite important advances, it is essential to examine the experiences of older LGBTIQ+ people, especially because they are vulnerable to dual discrimination in old age owing to a combination of homophobia and ageism. This study involved an analysis of social ties based on the Convoy Model, to understand how different life courses have influenced the structuring of social networks in old age among gay men and trans women in Chile. Framed within the context of broader research into four axes of diversity in ageing, this study reports the results of thirteen biographies of older people (ten gay men and three trans women). In-depth interviews were conducted using a biographical approach in which the social links that accompany the life course are deepened. A thematic analysis strategy was applied and the interview data were processed through NVivo. The findings show three concentric circles surrounding the participants: closest (made up of partner, immediate family and chosen family), closer (made up biological and extended family) and close (made up of peers and neighbours). The older people are integrated into social networks with diverse compositions, share closeness and intimacy, receive emotional, informational and instrumental social support, and are active providers of reciprocal support. However, the study notes certain risk factors, such as the difficulty of cohabiting and maintaining relationships with a partner. Participants living alone reported fearing an absence of instrumental support during more advanced stages of the ageing process.

NCCN guideline-concordant cancer care in Sub-Saharan Africa A population-based multi-country study of five cancers.

To assess population-based quality of cancer care in Sub-Saharan Africa and to identify specific gaps and joint opportunities, we assessed concordance of diagnostic and treatment with NCCN harmonized guidelines for leading cancer types in 10 countries. Adult patients with female breast cancer (BC), cervical cancer (CC), colorectal cancer (CRC), Non-Hodgkin lymphoma (NHL) and prostate cancer (PC) were randomly drawn from 11 population-based cancer registries. Guideline concordance of diagnostics and treatment was assessed using clinical records. In a sub-cohort of 906 patients with potentially curable cancer (stage I-III BC, CC, CRC, PC, aggressive NHL (any stage)) and documentation for >1 month after diagnosis, we estimated factors associated with guideline-concordant treatment or minor deviations (GCT). Diagnostic information as per guidelines was complete for 1030 (31.7%)of 3246 patients included. In the sub-cohort with curable cancer, GCT was documented in 374 (41.3%, corresponding to 11.7% of 3246 included in the population-based cohort): aggressive NHL (59.8%/9.1% population-based), BC (54.5%/19.0%), PC (39.0%/6.1%), CRC (33.9%/9.5%), and CC (27.8%/11.6%). GCT was most frequent in Namibia (73.1% of curable cancer subset/32.8% population-based) and lowest in Kampala, Uganda (13.5%/3.1%). GCT was negatively associated with poor ECOG status, locally advanced stage, origin from low HDI countries, and a diagnosis of CRC or CC. Quality of diagnostic workup and treatment showed major deficits, with considerable disparities among countries and cancer types. Improved diagnostic services are necessary to increase the share of curable cancer in SSA. Treatment components within NCCN guidelines synergetic for several cancers should be prioritized.

Differences in characteristics and outcomes between early-onset colorectal cancer and late-onset colorectal cancers

IntroductionColorectal cancer (CRC) represents a significant health burden worldwide, with a notable increase in early-onset colorectal cancer (EOCRC) cases, defined as those diagnosed before the age of 50 years. Materials and methodsUsing data from Taiwan's national cancer registry and a retrospective cohort from Chang Gung Memorial Hospital, this study analyzed CRC cases diagnosed between 2008 and 2019. The analysis compared the EOCRC and late-onset CRC (LOCRC) groups in terms of clinicopathological characteristics, pre-diagnostic symptoms, and survival outcomes. ResultsThe analysis revealed a continuous increase in the annual incidence of EOCRC, with colon cancer and rectal cancer rising by 3.2 % and 3.3 %, respectively. Patients with EOCRC presented with more aggressive disease characteristics, such as signet-ring cell adenocarcinoma, mucinous adenocarcinoma, and poorly differentiated grade. Advanced stages at diagnosis, stages III and IV, were more common with EOCRC (62.4 %) than with LOCRC (50.3 %). Patients with EOCRC reported rectal bleeding, changes in bowel habits, and abdominal pain more frequently than those in the LOCRC group. There is a strong association between stool-related symptoms and left-sided CRC. Despite similar surgical outcomes, the 5-year cancer-specific survival rate of patients with stage IV EOCRC was significantly lower than that of patients with LOCRC (32.8 % vs. 51.9 %, p = 0.012). ConclusionThis study highlights a persistent rise in the incidence of EOCRC, with patients presenting with more aggressive disease and experiencing inferior survival. These findings underscore the importance of heightened awareness and early detection strategies for CRC, especially in younger populations, to improve the prognosis.

Managing malignant sublingual gland tumors: a single institution experience with 23 patients

BackgroundDue to the relative rarity of malignant sublingual gland tumors, diagnosing and treating them clinically pose challenges. Hence, there’s a need to explore the pathological types, characteristics, treatment methods, and prognosis of primary malignant tumors of the sublingual gland to improve our understanding and management of these rare yet highly malignant conditions.MethodsThis study reviewed cases of primary malignant sublingual gland tumors, analyzing their characteristics. The treatment methods included surgical excision, with additional radiotherapy, or brachytherapy for advanced stages or positive surgical margins. The study also summarized different treatment approaches, including lymph node dissection and soft tissue reconstruction using free flaps such as the anterolateral thigh flap and forearm flap.ResultsWe have gathered 23 cases of sublingual gland malignancies treated at the Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, from January 2013 to May 2024. The most common pathological types were adenoid cystic carcinoma and mucoepidermoid carcinoma, with rare cases of mucosa-associated lymphoid tissue (MALT) lymphoma and nonspecific salivary gland clear cell carcinoma. Early diagnosis and surgical intervention were crucial for a favorable prognosis. Marginal mandibulectomy was necessary for cases involving the mandible. Patients with positive preoperative lymph node detection required cervical lymph node dissection. Extensive tissue defects in the floor of the mouth were effectively reconstructed with free flaps to prevent oral-mandibular fistula.ConclusionSurgical excision remains the preferred treatment for malignant sublingual gland tumors. Early diagnosis and comprehensive surgical management are essential for improving prognosis. The study’s limitations include a small sample size and short follow-up duration, necessitating further research with larger clinical samples to confirm these findings.

Integrative genomics unveils basement membrane-related diagnostic markers and therapeutic targets in esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) is often diagnosed at advanced stages due to the inherent limitations of current screening methodologies. Central to evaluating tumor invasion and prognostic assessment in ESCC is the integrity of the basement membrane (BM). However, current research on the implications of BM-related genes (BMRGs) in diagnosing ESCC remains sparse.MethodsWe performed a comprehensive analysis using single-cell RNA-sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database, alongside gene expression profiles acquired from GEO and The Cancer Genome Atlas (TCGA) databases. This identified differentially expressed BMRGs in ESCC. Employing LASSO, RF, and SVM-RFE, we selected potential BM biomarkers and crafted a diagnostic nomogram for ESCC, validated by ROC curves and AUC values. We also explored immune infiltration and biological mechanisms through consensus clustering and GSVA, and utilized single cell trajectory analysis and GSCALite to study gene distributions and pathways. In vitro experiments further elucidated the role of these genes in ESCC carcinogenesis.ResultsHere, we discovered that ESCC cell types exhibited markedly elevated BM-related scores. Our analysis pinpointed seven BM genes upregulated and linked to immune infiltration, showcasing unique gene expression profiles and varying immune cell densities across the BM-related subtypes. Furthermore, a robust positive correlation was observed between these genes expression and EMT activity. The knockdown of BGN significantly suppressed cell proliferation, migration, invasion, while also augmenting cell viability following chemotherapy drug treatment.ConclusionOur study identified seven key BMRGs (BGN, LAMB3, SPARC, MMP1, LUM, COL4A1, and NELL2) and established a diagnostic nomogram for ESCC. Of noteworthy significance is the discovery of BGN as a promising drug target, indicating a novel strategy for future clinical combination therapies in ESCC.

Reduced retinol (vitamin A) and α-tocopherol (vitamin E) blood levels and increased myeloperoxidase (MPO) activity in children with high myopia

The study assessed selected parameters of redox status in the plasma of patients suffering from high myopia (HM). Thirty-five children with mean age 13.7 ± 2.7 years with HM and 40 healthy children were included. Plasma redox status parameters were determined using colorimetric kits. The levels of retinol, α-tocopherol and coenzyme Q10 were determined with a high-performance liquid chromatograph. Negative correlations were observed between the concentrations of retinol and the axial length of the eye (r = − 0.514 p < 0.001). Increased myeloperoxidase (MPO) activity (p < 0.018), and decreased concentrations of retinol (p < 0.001) and α-tocopherol (p < 0.023) in patients with HM and the axial length of the eye > 26 mm compared to controls were established. Significantly lower retinol and α-tocopherol concentrations were found in patients with the axial length of the eye > 26 mm compared to those with the axial length of the eye ≤ 26 mm (p < 0.001, p < 0.021, respectively). Increased MPO activity in advanced stages of HM may confirm an inflammatory process in HM patients. Reduced retinol and α-tocopherol concentrations and their link to disease progression indicate a need for monitoring their levels and supplementation in children with HM.

White Matter Microstructure Changes Revealed by Diffusion Kurtosis and Diffusion Tensor Imaging in Mutant Huntingtin Gene Carriers.

Diffusion magnetic resonance imaging (dMRI) has revealed microstructural changes in white matter (WM) in Huntington's disease (HD). To compare the validities of different dMRI, i.e., diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) in HD. 22 mutant huntingtin (mHTT) carriers and 14 controls were enrolled. Clinical assessments and dMRI were conducted. Based on CAG-Age Product (CAP) score, mHTT carriers were categorized into high CAP (hCAP) and medium and low CAP (m& lCAP) groups. Spearman analyses were used to explore correlations between imaging parameters in brain regions and clinical assessments. Receiver operating characteristic (ROC) was used to distinguish mHTT carriers from control, and define the HD patients at advanced stage. Compared to controls, mHTT carriers exhibited WM changes in DKI and DTI. There were 22 more regions showing significant differences in HD detected by MK than FA. Only MK in five brain regions showed significantly difference between any two group, and negatively correlated with the disease burden (r = -0.80 to -0.71). ROC analysis revealed that MK was more sensitive and FA was more specific, while Youden index showed that the integration of FA and MK gave rise to higher authenticities, in distinguishing m& lCAP from controls (Youden Index = 0.786), and discerning different phase of HD (Youden Index = 0.804). Microstructural changes in WM occur at early stage of HD and deteriorate over the disease progression. Integrating DKI and DTI would provide the best accuracies for differentiating early HD from control and identifying advanced HD.

Diet and selected stimulants as factors promoting carcinogenesis in oral cancer

Introduction and purpose Oral cancer belongs to a heterogeneous group of head and neck cancers. In many cases, it is detected at an advanced stage, which translates into a relatively high mortality rate among patients. For this reason, the identification of risk factors promoting carcinogenesis is of great importance in terms of prevention. The purpose of our study is to demonstrate the relationship between the type of diet consumed and the intake of stimulants and the risk of developing oral cancer. State of knowledge This article is an overview of selected dietary ingredients and stimulants - tobacco, alcohol and betel, presenting their possible effects on the oral area. We have presented both dietary products known for their harmfulness and those with health-promoting effects. Material and method In our work, we focused on analyzing medical literature available on PubMed and Google Scholar. The sources we have chosen are based on studies conducted in epidemiology, biochemistry and oncology. Summary Dietary habits and ingested stimulants have a direct impact on the development of oral cancer. Depending on the content of various components, the diet may exhibit protective properties or promote carcinogenesis. On the other hand, chronic habitual use of certain substances has been found to be a strong factor in increasing the risk of oral malignancies. Therefore, efforts should be made to raise public awareness of the potential consequences of pro-inflammatory diets and stimulants intake.

A spatiotemporal comparative analysis on tumor immune microenvironment characteristics between neoadjuvant chemotherapy and preoperative immunotherapy for ESCC

The average five-year survival rate for esophageal cancer, a common malignant tumor of the digestive system, is barely 20%. The majority of esophageal squamous cell carcinoma (ESCC) patients had already progressed to a locally advanced or even advanced stage at initial diagnosis, making routine surgery ineffective. Chemotherapy and immunotherapy are important neoadjuvant treatments for ESCC, however, it remains unknown how treatment will affect the immunological microenvironment, especially at the spatial level. Here, we presented the TME characters of ESCC from the temporal and spatial dimensions using scRNA-seq and ST, investigated the changes of immune cell clusters in the TME under neoadjuvant chemotherapy and preoperative immunotherapy, and explored the potential mechanisms. It was found that compared with chemotherapy, immunotherapy combined with chemotherapy increased the level of T cell proliferation, partially restored the function of exhausted T cells, induced the expansion of specific exhausted CD8 T cells, increased the production of dendritic cells (DCs), and supported the immune hot microenvironment of the tumor. We also found that CD52 and ID3 have potential as biomarkers of ESCC. Particularly, CD52 may be served as a predictor of the efficacy to screen the advantaged population of different regimens. Through multiple pathways, CAF2 and CAF5’s antigen-presenting role affected the other fibroblast clusters, resulting in malignant transformation. We analyzed the immune microenvironment differences between the two regimens to provide a more thorough description of the ESCC microenvironment profile and serve as a foundation for customized neoadjuvant treatment of ESCC.

Palliative care in terminally ill advanced chronic liver disease patients.

While mortality rates from advanced chronic liver disease (ACLD) are rapidly increasing, patients with an advanced disease stage have acomparable or even higher symptom burden than those with other life-limiting diseases. Although evidence is limited there is increasing recognition of the need to improve care for patients with ACLD; however, there are many limiting factors to providing good palliative care for these patients, including unpredictable disease progression, the misconception of palliative care and end of life care as being equivalent, alack of confidence in prescribing medication and alack of time and resources. Health professionals working with these patients need to develop the skills to ensure effective palliative care, while referral to specialized palliative care centers should be reserved for patients with complex needs. Basic palliative care, along with active disease management, is best delivered by the treating hepatologists. This includes discussions about disease progression and advance care planning, alongside the active management of disease complications. Liver disease is closely associated with significant social, psychological, and financial burdens for patients and their caregivers. Strategies to engage the discussion in multidisciplinary teams early in disease progression help to ensure addressing these issues proactively. This review summarizes the evidence on palliative care for patients with ACLD, provides examples of current best practice and offers suggestions on how disease-modifying and palliative care can coexist, to ensure that patients do not miss opportunities for quality of life improving interventions.

Unraveling the Mechanisms of Magnesium Supplementation in Alleviating Chronic Kidney Disease Complications and Progression: Balancing Risks and Benefits.

Chronic kidney disease (CKD) is a major cause of death and disability worldwide. It is usually diagnosed at early levels because of its slow progression. Treatment should consider CKD complications (such as electrolyte level imbalance, vascular calcification, and bone mineral disorders), as well as the development of CKD itself. Large-scale studies have shown that current treatment guidelines are nearly ineffective and fail to achieve treatment goals. Guidelines have not paid as much attention to magnesium (Mg) as the other electrolytes, while Mg has a significant role in the treatment goals of CKD. Hypomagnesemia is the only electrolyte imbalance that is equally prevalent in all stages of CKD. A lower plasma Mg level in each stage of CKD is associated with a higher risk of CKD progression and cardiac events. Magnesium exerts its effects both directly and via other ions. Mg supplementation increases insulin sensitivity while reducing proteinuria and inflammation. It lowers blood pressure and inhibits vascular calcification primarily because of its effects on calcium and phosphate, respectively. Vitamin D supplementation for low-active vitamin D in CKD patients increases vascular calcification and cardiac events, but magnesium supplementation enhances vitamin D levels and activity without increasing the risk of cardiac events. However, careful attention is required due to the potential threats of hypermagnesemia, particularly in advanced CKD stages. Starting magnesium supplementation early in patients' treatment plans will result in fewer side effects and more advantages. More original research is needed to determine its optimal dose and serum levels.

Takotsubo syndrome in a Sardinian amyotrophic lateral sclerosis cohort.

Amyotrophic lateral sclerosis (ALS) is known to be associated with varying degrees of autonomic and cardiovascular dysfunction. Recent case reports showed that ALS may be linked to Takotsubo syndrome (TTS). We assessed the frequency of TTS in an incident ALS cohort from Sardinia, Italy, and investigated the relationship of TTS with ALS course. We retrospectively examined a 10-year (2010-2019) incident cohort of ALS patients of Sardinian ancestry, reported TTS frequency and patients' clinical characteristics. Following, we checked for TTS among patients with ALS onset after 2019 and focused on the same features as for the incident cohort. Our incident cohort included 344 ALS patients and 5 of them (1.45%) developed TTS. All were female and their median onset age was 71.5years (IQR 62.75-77). Two patients had spinal and three bulbar onset, though all patients had bulbar involvement and were at an advanced stage of disease (ALSFRS ≤ 25, King's ≥ 3) at TTS diagnosis. We identified a potential TTS trigger in three patients (hospitalization for PEG placement, pneumonia). Among patients who had ALS onset after 2019, we identified a further TTS case and described it. TTS is not a rare condition in ALS. Female sex, bulbar involvement, and later age of disease onset may be important risk factors for developing this cardiac condition and a physical or psychological trigger is often observed. Despite autonomic dysfunction in ALS has been already demonstrated, the precise physiopathological mechanism underlying TTS needs to be further clarified.

Shared etiology of Mendelian and complex disease supports drug discovery

BackgroundDrugs targeting disease causal genes are more likely to succeed for that disease. However, complex disease causal genes are not always clear. In contrast, Mendelian disease causal genes are well-known and druggable. Here, we seek an approach to exploit the well characterized biology of Mendelian diseases for complex disease drug discovery, by exploiting evidence of pathogenic processes shared between monogenic and complex disease. One way to find shared disease etiology is clinical association: some Mendelian diseases are known to predispose patients to specific complex diseases (comorbidity). Previous studies link this comorbidity to pleiotropic effects of the Mendelian disease causal genes on the complex disease.MethodsIn previous work studying incidence of 90 Mendelian and 65 complex diseases, we found 2,908 pairs of clinically associated (comorbid) diseases. Using this clinical signal, we can match each complex disease to a set of Mendelian disease causal genes. We hypothesize that the drugs targeting these genes are potential candidate drugs for the complex disease. We evaluate our candidate drugs using information of current drug indications or investigations.ResultsOur analysis shows that the candidate drugs are enriched among currently investigated or indicated drugs for the relevant complex diseases (odds ratio = 1.84, p = 5.98e-22). Additionally, the candidate drugs are more likely to be in advanced stages of the drug development pipeline. We also present an approach to prioritize Mendelian diseases with particular promise for drug repurposing. Finally, we find that the combination of comorbidity and genetic similarity for a Mendelian disease and cancer pair leads to recommendation of candidate drugs that are enriched for those investigated or indicated.ConclusionsOur findings suggest a novel way to take advantage of the rich knowledge about Mendelian disease biology to improve treatment of complex diseases.