Biomedicines最新文献

Background/Objectives: Pembrolizumab, an immune checkpoint inhibitor targeting programmed death 1 (PD-1), is a widely employed therapy for various gastrointestinal (GI) cancers. We conducted a systematic review of clinical trials investigating pembrolizumab monotherapy in GI cancer patients to assess the spectrum and incidence of immune-related adverse events (irAEs) associated with pembrolizumab. Methods: A comprehensive search of PubMed/MEDLINE was performed to identify clinical trials investigating pembrolizumab monotherapy in GI cancer patients. Primary endpoints included the incidence of grade 3 or higher irAEs and the rate of treatment discontinuation due to irAEs. Secondary endpoints encompassed the incidence of any-grade irAEs, as well as specific irAEs. Results: Data extraction and analysis were performed on 25 articles. The analysis included 3101 patients with a median age of 62 years (range 53-68), with 30.2% being female. Tumor types encompassed were colorectal (12%), esophagogastric (46%), hepatocellular carcinoma (24%), and other GI tumor types (18%). The rate of treatment discontinuation due to irAEs was 6.8%. The most prevalent grade 3 or higher irAEs were hepatitis (3.6%), pneumonitis (0.8%), and colitis (0.7%). Death attributed to irAEs was infrequent (0.9%). Conclusions: In patients with GI cancers treated with pembrolizumab monotherapy, severe toxicities are infrequent, and irAEs leading to treatment discontinuation or death are uncommon.

Background and objectives: The interplay of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and Clostridioides difficile infection (CDI) poses a critical clinical challenge. The resultant inflammatory milieu and its impact on outcomes remain incompletely understood, especially among vulnerable subgroups such as elderly patients, those with diabetes, and individuals with cancer. This study aimed to characterize inflammatory markers and composite inflammatory severity scores-such as Acute Physiology and Chronic Health Evaluation II (APACHE II), Confusion, Urea, Respiratory rate, Blood pressure, and age ≥ 65 years (CURB-65), National Early Warning Score (NEWS), and the Systemic Immune-Inflammation Index (SII)-in hospitalized Coronavirus Disease 2019 (COVID-19) patients with and without CDI, and to evaluate their prognostic implications across key clinical subgroups.

Methods: We conducted a retrospective, single-center study of 240 hospitalized adults with Reverse Transcription Polymerase Chain Reaction (RT-PCR)-confirmed COVID-19 between February 2021 and March 2023. Of these, 98 had concurrent CDI. We collected baseline demographics, comorbidities, and laboratory parameters including C-reactive protein (CRP), Interleukin-6 (IL-6), ferritin, neutrophil and lymphocyte counts, albumin, platelet counts, and calculated indices (C-reactive protein to Albumin Ratio (CAR), Neutrophil-to-Lymphocyte Ratio (NLR), Prognostic Nutritional Index (PNI), SII). Patients were stratified by CDI status and analyzed for inflammatory marker distributions, severity scores (APACHE II, CURB-65, NEWS), and outcomes (Intensive Care Unit (ICU) admission, mechanical ventilation, mortality). Subgroup analyses included diabetes, elderly (≥65 years), and cancer patients. Statistical comparisons employed t-tests, chi-square tests, and logistic regression models.

Results: Patients with CDI demonstrated significantly higher CRP, IL-6, SII, and CAR, coupled with lower albumin and PNI (p < 0.05). They also had elevated APACHE II, CURB-65, and NEWS scores. CDI-positive patients experienced increased ICU admission (38.8% vs. 20.5%), mechanical ventilation (24.5% vs. 12.9%), and mortality (22.4% vs. 10.6%, all p < 0.05). Subgroup analyses revealed more pronounced inflammatory derangements and worse outcomes in elderly, diabetic, and cancer patients with CDI.

Conclusions: Concurrent CDI intensifies systemic inflammation and adverse clinical trajectories in hospitalized COVID-19 patients. Elevations in inflammatory markers and severity scores predict worse outcomes, especially in high-risk subgroups. Early recognition and targeted interventions, including infection control and supportive measures, may attenuate disease severity and improve patient survival.

Malignant melanoma (MM) is a malignant tumor, resulting from mutations in melanocytes of the skin and mucous membranes. Its mortality rate accounts for 90% of all dermatologic tumor mortality. Traditional treatments such as surgery, chemotherapy, and radiotherapy are unable to achieve the expected results due to MM's low sensitivity, high drug resistance, and toxic side effects. As treatment advances, immunotherapy and targeted therapy have made significant breakthroughs in the treatment of MM and have demonstrated promising application prospects. However, the heterogeneity of tumor immune response causes more than half of patients to not benefit from clinical immunotherapy and targeted therapy, which delays the patient's condition and causes them to suffer adverse immune events' side effects. The combination of immunotherapy and targeted therapy can help improve therapeutic effects, delay drug resistance, and mitigate adverse effects. This review provides a comprehensive overview of the current development status and research progress of immune checkpoints, targeted genes, and their inhibitors, with a view to providing a reference for the clinical treatment of MM.

Background/Objectives: Aging is associated with structural and functional changes in the heart, including hypertrophy, fibrosis, and impaired contractility. Cellular mechanisms such as senescence, telomere shortening, and DNA damage contribute to these processes. Nuclear factor kappa B (NF-κB) has been implicated in mediating cellular responses in aging tissues, and increased NF-κB expression has been observed in the hearts of aging rodents. Therefore, NF-κB is suspected to play an important regulatory role in the cellular and molecular processes occurring in the heart during aging. This study investigates the in vivo role of NF-κB in aging-related cardiac alterations, focusing on senescence and associated cellular events. Methods: Young and old wild-type (WT) and transgenic male mice with cardiomyocyte-specific NF-κB suppression (3M) were used to assess cardiac function, morphology, senescence markers, lipofuscin deposition, DNA damage, and apoptosis. Results: Kaplan-Meier analysis revealed reduced survival in 3M mice compared to WT. Echocardiography showed evidence of eccentric hypertrophy, and both diastolic and systolic dysfunction in 3M mice. Both aged WT and 3M mice exhibited cardiac hypertrophy, with more pronounced hypertrophic changes in cardiomyocytes from 3M mice. Additionally, cardiac fibrosis, senescence-associated β-galactosidase activity, p21 protein expression, and DNA damage (marked by phosphorylated H2A.X) were elevated in aged WT and both young and aged 3M mice. Conclusions: The suppression of NF-κB in cardiomyocytes leads to pronounced cardiac remodeling, dysfunction, and cellular damage associated with the aging process. These findings suggest that NF-κB plays a critical regulatory role in cardiac aging, influencing both cellular senescence and molecular damage pathways. This has important implications for the development of therapeutic strategies aimed at mitigating age-related cardiovascular diseases.

Background: Cholera is a diarrheal disease prevalent in populations without access to clean water. Cholera is caused by Vibrio cholerae, which colonizes the upper small intestine in humans once ingested. A growing number of studies suggest that the gut microbiome composition modulates animal behavior. Zebrafish are an established cholera model that can maintain a complex, mature gut microbiome during infection. Larval zebrafish, which have immature gut microbiomes, provide the advantage of high-throughput analyses for established behavioral models. Methods: We identified the effects of V. cholerae O1 El Tor C6706 colonization at 5 days post-fertilization (dpf) on larval zebrafish behavior by tracking startle responses at 10 dpf. We also characterized the larval gut microbiome using 16S rRNA sequencing. V. cholerae-infected or uninfected control groups were exposed to either an alternating light/dark stimuli or a single-tap stimulus, and average distance and velocity were tracked. Results: While there was no significant difference in the light/dark trial, we report a significant decrease in distance moved for C6706-colonized larvae during the single-tap trial. Conclusion: This suggests that early V. cholerae colonization of the larval gut microbiome has a dampening effect on sensorimotor function, supporting the idea of a link between the gut microbiome and behavior.

Diabetes is a chronic metabolic disorder whose prevalence increases every year, affecting more than 530 million adults worldwide. Type 1 (T1D) and type 2 diabetes (T2D), the most common forms of diabetes, are characterized by the loss of functional pancreatic β-cells, mostly due to apoptosis. B-cell leukemia/lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), two anti-apoptotic proteins belonging to the Bcl-2 family, are crucial for regulating the intrinsic pathway of apoptosis. However, over the years, they have been implicated in many other cellular processes, including intracellular Ca²⁺ homeostasis and the regulation of mitochondrial metabolism. Thus, understanding the biological processes in which these proteins are involved may be crucial to designing new therapeutic targets. This review summarizes the roles of Bcl-2 and Bcl-xL in apoptosis and metabolic homeostasis. It focuses on how the dysregulation of Bcl-2 and Bcl-xL affects pancreatic β-cell function and survival, and the consequences for diabetes development.

Under normal conditions, potassium is predominantly found within cells. The concentration gradient of sodium and potassium ions between intracellular and extracellular spaces enables signal transmission through membrane depolarization. The disruption of this transcellular process leads to elevated potassium ion levels in the extracellular space, and thus in the blood, a condition known as hyperkalemia. Clinically, hyperkalemia may present as cardiac arrhythmias, muscle weakness, and palpitations. The post-mortem accumulation of potassium ions in various human tissues and organs, such as the heart, liver, kidneys, lungs, and vitreous body, particularly in cases of overdose, has been an area of research interest for years. Unfortunately, deaths caused by hyperkalemia are difficult to identify due to their non-specific symptoms and are often misinterpreted as cardiovascular-related. Furthermore, most potassium ion concentration tests developed in recent years are non-specific, have limitations, or are based on outdated techniques. Consequently, alternative methods, such as histopathological tissue analysis, potassium concentration assessment in the vitreous body, and aldosterone level measurement, show promise for improving the post-mortem detection of exogenous hyperkalemia.

Background/Objectives: The excitability of skeletal muscle is a less-known post-mortem supravital phenomenon in human bodies, and it can be used to estimate the post-mortem interval. We conducted a field study in the Netherlands to investigate the applicability of muscle excitability (SMR) by mechanical stimulation for estimating the post-mortem interval in daily forensic practice. Knowledge concerning the post-mortem cell mechanisms accounting for the post-mortem excitability of skeletal muscle is lacking. Cell mechanisms are the specific intracellular and biochemical processes responsible for post-mortem muscle excitability. Methods: We have studied the theoretical backgrounds of the cell mechanisms that might be responsible for post-mortem muscle excitability, by performing literature research via the databank PubMed. Results: Based on the current available literature, in our opinion the intracellular changes in muscle cells that are responsible for SMR resemble the intracellular processes responsible for muscle fatigue due to energy exhaustion in the living. Conclusions: We hypothesize two pathways, depending on the level of energy in the muscle cell, that could be responsible for post-mortem muscle excitability by mechanical stimulation.

Introduction: Popliteal cysts (PCs) are occasionally accompanied by knee osteoarthritis (OA) and varus malalignment. However, whether concomitant arthroscopic excision of PCs with medial open-wedge high tibial osteotomy (MOWHTO) improves the osteoarthritic environment remains unclear. Therefore, this study assessed serial changes in C-size, medial meniscus extrusion (MME), and cartilage status for up to 2 years following an MOWHTO. Methods: This study retrospectively used serial magnetic resonance imaging (MRI) evaluations to assess 26 consecutive patients who underwent MOWHTO. Of the 26 patients, six with preoperative PCs were included. Based on the arthroscopic findings at the time of the MOWHTO, concomitant meniscal and chondral lesions, and whether or not partial meniscectomy was performed, were evaluated. All patients underwent second-look arthroscopy with plate removal 2 years postoperatively. The PC size, MME, and cartilage sub-scores in the medial compartment of the whole-organ MRI score (WORMS) were assessed by serial MRI preoperatively and at 3, 6, 18, and 24 months postoperatively. The recurrence of PCs and clinical outcomes, including the Rauschning-Lindgren grade, were also evaluated when serial MRI was performed. Moreover, changes in cartilage status were assessed using two-stage arthroscopy. Results: All patients underwent concomitant partial meniscectomy for medial meniscal tears in the posterior horn. A significant decrease in the mean size of preoperative PCs (27.4 ± 22.3 mm) was noted from 3 months postoperatively (8.7 ± 7.6 mm, p = 0.018), and thereafter. The mean size of PCs further decreased with time until 2 years (1.5 ± 4.0 mm, p = 0.018) following an MOWHTO with partial meniscectomy. Moreover, significant improvements in the MME and WORMS values were noted from 3 to 24 months postoperatively. Meanwhile, no PC recurrence occurred during the follow-up period and the preoperative Rauschning-Lindgren grade improved significantly with time after MOWHTO (p = 0.026). Furthermore, the two-stage arthroscopic assessments showed significant improvements in ICRS grade in the medial femoral condyle (p = 0.038). Conclusions: After an MOWHTO with partial meniscectomy, PCs decreased with time up to 2 years postoperatively; no recurrence occurred during the follow-up period, although cyst excision was not concomitantly performed. Furthermore, the reduction in PCs corresponded with improvements in MME and chondral lesions in the knee joint following the MOWHTO.

Background: The objective was to test the generalisability of electroencephalography (EEG) markers of future pain using two independent datasets. Methods: Datasets, A [N = 20] and B [N = 35], were collected from participants with subacute spinal cord injury who did not have neuropathic pain at the time of recording. In both datasets, some participants developed pain within six months, (PDP) will others did not (PNP). EEG features were extracted based on either band power or Higuchi fractal dimension (HFD). Three levels of generalisability were tested: (1) classification PDP vs. PNP in datasets A and B separately; (2) classification between groups in datasets A and B together; and (3) classification where one dataset (A or B) was used for training and testing, and the other for validation. A novel normalisation method was applied to HFD features. Results: Training and testing of individual datasets achieved classification accuracies of >80% using either feature set, and classification of joint datasets (A and B) achieved a maximum accuracy of 86.4% (HFD, support vector machine (SVM)). With normalisation and feature reduction (principal components), the validation accuracy was 66.6%. Conclusions: An SVM classifier with HFD features showed the best robustness, and normalisation improved the accuracy of predicting future neuropathic pain well above the chance level.