Early Stages Of Treatment Research Articles

Early effectiveness and safety analysis of belimumab in addition to standard treatment in patients with systemic lupus erythematosus.

This study aimed to evaluate the early effectiveness and safety of belimumab in addition to standard therapy in patients with systemic lupus erythematosus (SLE) for 24 weeks. This retrospective study was conducted with 60 adult patients with active SLE between June 2020 and August 2022. The patients either received intravenous belimumab in addition to standard therapy (n=31; 24 females, 7 males; mean age: 33.7±14.1 years; range, 18 to 52 years) or only standard therapy (n=29; 22 females, 7 males; mean age: 34.1±13.4 years; range, 19 to 66 years) for 24 weeks. Outcome measures, including safety and effectiveness (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index [SELENA-SLEDAI]), changes in biomarkers (double-stranded DNA [deoxyribonucleic acid]), serum complement levels, and immunoglobin G (IgG) were recorded. Adverse events were recorded. Baseline demographic and clinical characteristics were similar between the two groups. More patients in the belimumab group achieved a reduction of ≥4 points in SELENA-SLEDAI at weeks 12 and 24 (week 12, 77.4% vs. 41.4%, p=0.008; week 24, 87.1% vs. 48.3%, p=0.002). The mean score of SELENA-SLEDAI was significantly lower in the belimumab group compared to the standard therapy group at week 12. However, a significant difference was not reached at week 24. Moreover, mean levels of serum C3 and C4 in the belimumab group were significantly higher than those in the standard therapy group at weeks 12 and 24. A higher proportion of patients in the belimumab group had a normal C3 level than in the standard therapy group. In addition, belimumab treatment resulted in a significant decrease in IgG levels at both weeks 12 and 24. At week 24, the belimumab group had a higher reduction in prednisone dose than the standard therapy group. Furthermore, the percentages of patients with more than 50% reduction in prednisone over baseline were significantly greater for belimumab versus standard therapy at week 12 (p=0.002). The occurrence of adverse events was similar between the two groups (standard therapy group, 44.8%; belimumab group, 51.6%). Intravenous belimumab was well tolerated and significantly improved disease activity in Chinese patients with SLE at the early stage of treatment. More importantly, belimumab treatment could result in a rapid reduction in prednisone dose as early as week 12.

Detection of renal cell hydronephrosis in ultrasound kidney images: a study on the efficacy of deep convolutional neural networks

In the realm of medical imaging, the early detection of kidney issues, particularly renal cell hydronephrosis, holds immense importance. Traditionally, the identification of such conditions within ultrasound images has relied on manual analysis, a labor-intensive and error-prone process. However, in recent years, the emergence of deep learning-based algorithms has paved the way for automation in this domain. This study aims to harness the power of deep learning models to autonomously detect renal cell hydronephrosis in ultrasound images taken in close proximity to the kidneys. State-of-the-art architectures, including VGG16, ResNet50, InceptionV3, and the innovative Novel DCNN, were put to the test and subjected to rigorous comparisons. The performance of each model was meticulously evaluated, employing metrics such as F1 score, accuracy, precision, and recall. The results paint a compelling picture. The Novel DCNN model outshines its peers, boasting an impressive accuracy rate of 99.8%. In the same arena, InceptionV3 achieved a notable 90% accuracy, ResNet50 secured 89%, and VGG16 reached 85%. These outcomes underscore the Novel DCNN’s prowess in the realm of renal cell hydronephrosis detection within ultrasound images. Moreover, this study offers a detailed view of each model’s performance through confusion matrices, shedding light on their abilities to categorize true positives, true negatives, false positives, and false negatives. In this regard, the Novel DCNN model exhibits remarkable proficiency, minimizing both false positives and false negatives. In conclusion, this research underscores the Novel DCNN model’s supremacy in automating the detection of renal cell hydronephrosis in ultrasound images. With its exceptional accuracy and minimal error rates, this model stands as a promising tool for healthcare professionals, facilitating early-stage diagnosis and treatment. Furthermore, the model’s convergence rate and accuracy hold potential for enhancement through further exploration, including testing on larger and more diverse datasets and investigating diverse optimization strategies.

The temporal progression of retinal degeneration and early-stage idebenone treatment in the Pde6brd1/rd1 mouse model of retinal dystrophy

Photoreceptor cell death, primarily through apoptosis, related to retinal disorders like retinitis pigmentosa (RP), would result in vision loss. The pathological processes and crucial mutant conditions preceding photoreceptor cell demise are not well understood. This study aims to conduct an in-depth examination of early-stage changes in the widely utilized Pde6brd1/rd1 (rd1) mouse model, which has Pde6b gene mutations representing autosomal recessive RP disorder. We investigated the morphology and ultrastructure of retinal cells, including second-order neurons, during the initial phase of disease progression. Our findings revealed that mitochondrial alterations in rod photoreceptors were present as a predeath mutant state as early as postnatal day 3 (P3). The bipolar and horizontal cells from the rd1 mouse retina exhibited significant morphological changes in response to loss of photoreceptor cells, indicating that second-order neurons rely on these cells for their structures. Subsequent oral administration of idebenone, a mitochondria-protective agent, enhanced retinal function and promoted both photoreceptor cell survival and inner retinal second-order synaptogenesis in rd1 mice at P14. Our findings offer a mechanistic framework, suggesting that mitochondrial damage acts as an early driver for photoreceptor cell death in retinal degeneration.

Clinical presentation and outcome of invasive mould disease in paediatric patients with acute lymphoblastic leukaemia

BackgroundChildhood acute lymphoblastic leukaemia (ALL) cure rates have improved, but invasive mould disease (IMD) remains a life-threatening complication. Here, we evaluate the epidemiology, clinical presentation, treatment and outcome of IMD in paediatric patients with ALL. MethodsPatients (1–18 years) treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol from 2012–2021 were analysed for probable and proven IMD. Data was extracted from the Dutch national registry and the electronic health care system. ResultsAmong 643 patients with ALL, 47 (7.3%) were diagnosed with a probable (n = 29) or proven (n = 18) IMD. Aspergillosis was diagnosed in 42 (89%) patients. Forty-one episodes (87%) occurred during the induction (n = 20) and first consolidation (n = 21) course. The median age at ALL diagnosis was 5 years [IQR 3–10] in the overall group versus 14 years [IQR 7–16] in the IMD group. Two-third of the patients did not receive mould-active prophylaxis. The most prevalent clinical symptoms at presentation were persistent fever and respiratory symptoms. The lungs were the most common site of infection with involvement in 44 (94%) patients, followed by the CNS in 16 (34%) patients. The 6-week and 12-week mortality rate after IMD diagnosis was 10.6% and 14.9%, respectively. Discussion and conclusionIn our paediatric cohort a notable incidence of probable and proven IMD was observed during the early stages of treatment. Remarkable is the high frequency of CNS involvement. These findings highlight the importance of effective prophylactic strategies and warrant early brain imaging.

Extracorporeal Methods of Hemocorrection in Patients with Abdominal Sepsis

BACKGROUND. Theoretical data convincingly support the use of extracorporeal hemocorrection (ECHC) methods in the treatment of sepsis. However, a large number of researchers have still not been able to convincingly prove the advantage of ECHC methods; there is no unanimity of opinion. We tried to analyze our own experience in using ECHC methods in the treatment of abdominal sepsis over the past 3 years. AIM OF STUDY. To analyze the use of ECHC methods in the early stages of treatment of abdominal sepsis, to determine whether their use had an advantage for survival. STUDY DESIGN. Prospective cohort. DESCRIPTION OF THE METHOD. In 50 cases (group 1), ECHC was performed early after surgery. The median time from admission to the intensive care unit after surgery to the start of ECHC was 25.3 (17.7; 36.5) hours. When determining the ECHC modality, we were guided by the individual approach and clinical experience of the ECHC specialist. Apheresis methods alone were performed in 8 % of patients (4/50), a combination of apheresis methods and renal replacement therapy was performed in 40 % (20/50), renal replacement therapy (RRT) methods were performed in 98 % (46/50), plasmapheresis/plasma exchange/selective plasma filtration were performed in 30 % (15/50), selective hemosorption of cytokines was performed in 4 % (2/50), selective hemosorption lipopolysaccharides was performed in 24 % (12/50). We analyzed outcomes, assessments of the severity of functional disorders and sepsis-associated organ dysfunction according to the APACHE scales II and SOFA and their dynamics, probabilities of outcomes depending on the scores on the indices (logistic regression); life times, cumulative survival rate (Kaplan-Meier method). SAMPLE CHARACTERISTICS. There were 113 patients after emergency laparotomy due to widespread peritonitis, abdominal sepsis, aged from 23 to 90 years. 67 men, 46 women. In 50 cases of observation (group 1), ECHC was performed in the early stages ; in 63 cases, methods of active hemocorrection were not used (group 2). In group 1 there were 35 patients with septic shock and 15 patients with stable hemodynamics (subgroup 1/shock and subgroup 1/sepsis). In group 2 there were 20 patients with shock and 43 with stable hemodynamics (subgroup 2/shock and subgroup 2/sepsis). RESEARCH RESULTS ECHC. Methods allowed survival of patients with more severe APACHE scores II and SOFA: in survivors in subgroup 1/shock Me 29 (24; 31) versus 23 (14; 26) in the subgroup 2/shock and 8 (4; 10) versus 4 (2; 6) points, p=0.048 and p = 0.010; with stable hemodynamics in survivors in subgroup 1/sepsis Me 20 (17; 22) versus 15 (11; 19) in subgroup 2/sepsis, p=0.016. ECHC changed the survival threshold in favor of more severe patients from 29 to 33 points; reduced the likelihood of an unfavorable outcome 1.2-fold for each point on the APACHE scale II and 1,276 times over the entire range of estimates; prolonged survival time in hemodynamically unstable patients at a significance level of p = 0.083, shifting the first quartile of survival from 1 to 12 days, the median from 12 to 20, the third quartile from 27 to 45 days. When performing ECHC, the cumulative survival rate was higher throughout the entire hospital observation period: 0.886 (95 % CI 0.780–0.939) in 2 days versus 0.700 (95 % CI 0.499–0.802); 0.800 (95 % CI 0.667–0.868) in 10 days versus 0.545 (95 % CI 0.325–0.658); 0.653 (95 % CI 0.494–0.734) in 14 days versus 0.416 (95 % CI 1.185–0.533). Overall mortality from all causes was 35.4 % (40/113), 67.3 (37/55) with shock, 5.2 % (3/58) with stable hemodynamics. The maximum risk of an unfavorable outcome occurred in the early stages: 30 % (12/40) of all deaths occurred in the first 4 days after surgery, 20 % (8/40) in the first 24 hours. In shock patients, 10-day mortality was lower when performing ECHC: 20.0 % (7/35) versus 45.0 % (9/20), p = 0.050, 1st stage. Fisher’s test, P = 0.38 insufficient. Hospital mortality in the shock subgroups was equal, all the advantages of ECHC achieved in the early stages were lost; although in most late outcomes the peritonitis was relieved; which was confirmed during the section. CONCLUSIONS. The power of the study was sufficient to identify statistically significant advantages of extracorporeal hemocorrection in the treatment of abdominal sepsis based on APACHE index estimates II and SOFA. For the Kaplan–Meier method, differences were obtained for shock patients at a significance level of 0.083; the number of observations must be doubled to detect statistically significant differences. The final results of hospital mortality require additional in-depth analysis, since in the later stages many deaths were not associated with abdominal sepsis and occurred with already resolved peritonitis. It is necessary to understand to what extent they were associated with experienced sepsis, and to what extent with comorbid pathology; whether there was an association with methods of extracorporeal hemocorrection.

Real-world clinical characteristics and treatment patterns among people with hepatocellular carcinoma in the United States (US) treated with resection or ablation.

436 Background: Treatment guidelines for early-stage hepatocellular carcinoma (eHCC) include therapies with curative intent comprising three primary strategies: liver transplantation, surgical resection, or ablation (for small lesions). However, many people experience HCC recurrence, with recurrence rates of up to approximately 80% within 5 years after resection. Furthermore, contemporary insights into the eHCC treatment landscape and post-recurrence treatment patterns in the real-world setting are lacking. This study was designed to assess demographic and clinical characteristics and treatment patterns for people with HCC who received resection or ablation as a proxy for defining early-stage disease. Methods: This was a retrospective observational cohort study of adults with HCC treated with resection or ablation in the US, conducted using linked electronic health records and healthcare claims from Optum’s de-identified Market Clarity Data. Index date was the date of the first observed resection or ablation between July 2016 and March 2021. Baseline characteristics were assessed in the 6-month period prior to index, and patients (pts) were followed until end of continuous enrolment in a medical and pharmacy plan, death, or data cut-off (September 2022), whichever occurred first. Demographic and clinical characteristics and treatment patterns, including subsequent treatments, were described. Results: A total of 649 pts met the study criteria and were included in the analyses. The median duration of follow-up was 23.0 months (range: 0.03–74.55 months). The mean age at index was 64.1 years (median 64.0 years), with a majority male gender (72.9%) and White race (65.5%). A total of 385 pts (59.3%) underwent ablation only, 242 pts (37.3%) underwent resection only, and 22 pts (3.4%) underwent both procedures at index. Transarterial embolization alone was received by 57 (8.8%) pts and was the most common embolization procedure received during follow-up, followed by transarterial chemoembolization alone in 46 (7.1%) pts and transarterial radioembolization in 46 (7.1%) pts. A total of 88 (13.6%) pts received systemic therapies for HCC (tyrosine kinase inhibitors, programmed cell death protein-1/programmed cell death-ligand 1/cytotoxic T-lymphocyte-associated antigen 4 inhibitors, or angiogenesis inhibitors) during follow-up. Conclusions: In this real-world cohort, ablation was the most received curative intent therapy for HCC. Among treatments received during follow-up, locoregional therapies were used most often, followed by systemic therapies. Although limited by its retrospective, observational nature, short duration of follow-up, and availability of data in the database, the results of this analysis provide a contemporary landscape of early-stage treatments for HCC in the real-world setting.

Effects of ultrasonic cavitation on microstructure and surface properties of Mn–Cu alloy

In the presented study, the effects of ultrasonic vibration on microstructure and surface properties of Mn–Cu alloy were investigated. At the early stage of ultrasonic cavitation treatment, grains of Mn–Cu alloy are refined, nanocrystals and amorphous bands are produced. As the ultrasonic cavitation treatment proceeds, the face-centered cubic structure is transformed into the body-centered tetragonal structure, and the martensitic phase transformation arises. The transformation is accompanied by plastic deformation and the formation of dislocations. The generation of martensite is caused by the stress and strain. Due to grain refinement, dislocations, and generation of martensite, the surface hardness of Mn–Cu alloy is enhanced, and the friction coefficient decreases. The resistance to wear is thereby improved.

Gynecological cancer during pregnancy-From a gyne-oncological perspective.

Gynecological cancer diagnosed during pregnancy requires accurate diagnosis and staging to determine optimal treatment based on gestational age. Cervical and ovarian cancers are the most common and multidisciplinary team collaboration is pivotal. Magnetic resonance imaging and ultrasound can be used without causing fetal harm. In cervical cancer, early-stage treatments can often be delayed until fetal lung maturation and cesarean section is recommended if disease prevails, in combination with a simple/radical hysterectomy and lymphadenectomy. Chemoradiotherapy, the recommended treatment for advanced stages, is not compatible with pregnancy preservation. Most gestational ovarian cancers are diagnosed at an early stage and consist of nonepithelial cancers or borderline tumors. Removal of the affected adnexa during pregnancy is often necessary for diagnosis, though staging can be performed after delivery. In selected cases of advanced cervical and ovarian cancers, neoadjuvant chemotherapy may be an option to allow gestational advancement but only after thorough multidisciplinary discussions and counseling.

Biomarkers in the early stage of PD-1 inhibitor treatment have shown superior predictive capabilities for immune-related thyroid dysfunction.

Hematological indicators in the early stage of PD-1 inhibitor treatment may show superior predictive ability of the occurrence of immune related adverse event (irAE) compared to the pre-treatment indicators, as the immune response is modulated during the PD-1 inhibitor treatment. The objective of this study was to investigate the predictive capabilities of biomarkers in the early treatment stage for immune related thyroid dysfunction (irTD), and explore the potential predictive cytokines. Medical records and blood test results of cancer patients treated with PD-1 inhibitor at a certain medical institution were collected. Logistic regression analysis was utilized to identify the predictive factors of irTD, ROC curves were plotted and the area under the curves (AUC) was calculated. Serum samples were collected before and during early treatment phase, cytokine detection was performed to explore potential predictive cytokines. A total of 264 patients were enrolled, 58 developed irTD (21.97%), including 31 patients with thyrotoxicosis and 27 with hypothyroidism. There were no significant differences in demographic characteristics, tumor types and PD-1 inhibitors between patients with and without irTD. Multivariate logistic analysis showed that anti-thyroglobulin antibody (TgAb) (OR=2.831, 95%CI: 1.077-7.443, P=0.035) and anti-thyroperoxidase antibody (TPOAb) (OR=9.565, 95%CI: 3.399-26.921, P=0.000) in the early treatment phase were independent predictive factors for irTD, the AUC of early-stage biomarkers was larger than that of pre-treatment (0.655 vs 0.571); low level of TSH at the early stage (OR=0.162, 95%CI: 0.077-0.341, P=0.000) was significantly correlated with thyrotoxicosis; female (OR=3.889, 95%CI: 1.457-10.380, P=0.007) and positive TPOAb (OR=8.678, 95%CI: 2.656-28.357, P=0.000) at the early stage were significantly correlated with hypothyroidism. The AUCs of early-stage biomarkers were larger than that of pre-treatment both in thyrotoxicosis (0.812 vs 0.637) and hypothyroidism patients (0.728 vs 0.710). The increase of IL-16 (adjusted P=0.004), IL-12p70 (adjusted P=0.014), IL-17 (adjusted P=0.014), CCL-15 (adjusted P=0.014) and IL-1a (adjusted P=0.021) in the early treatment phase were positively correlated with irTD. Biomarkers at the early stage of PD-1 inhibitor treatment could predict irTD, and demonstrated stronger predictive ability compared to pre-treatment biomarkers. IL-16, IL-12p70, IL-17, CCL-15 and IL-1a could serve as potential predictive biomarkers for irTD.

Racial Disparities in Surgical Management For Early-Stage Laryngeal Squamous Cell Carcinoma and Recurrent Dysplasia.

The aim of this study is to evaluate the association between race and the treatment of laryngeal dysplasia and early-stage laryngeal squamous cell carcinoma (LSCC). Retrospective Cohort Study. Large multispecialty academic medical center. Patients were treated for laryngeal dysplasia or LSCC between September 2019 and September 2022. A retrospective chart review was conducted to collect demographic and clinical information. Two-sample t tests, chi-square tests, and linear regression models were used to compare characteristics (α = 0.05). Analyses were performed in STATA 17. Sixty-fivepatients were identified that underwent potassium titanyl phosphate (KTP) transoral laser microsurgery for management of early-stage LSCC (n = 29) or dysplasia (n = 36). The cohort consisted of 23 Black and 42 White patients. No significant difference was found in age, alcohol or tobacco use, rate of adjuvant radiotherapy, stage of disease, nor insurance status between the 2 groups. White patients underwent more procedures to address initial disease and subsequent recurrent dysplasia on average than Black patients (2.52 vs 1.52, P = .02). This remained true after adjusting for demographic and clinical characteristics and insurance status in a linear regression model. While Black patients were more likely to be lost to follow-up than White patients (30.4% vs 9.5%, P = .03), the average number of procedures between the groups still differed significantly (2.63 vs 1.56, P = .04) when controlling for those lost to follow-up. The findings presented here highlight potential inequities that exist for racial minorities at early stages of treatment and in addressing premalignant conditions, which may contribute to the known downstream disparities in laryngeal cancer outcomes.

Liver injury due to endothelin receptor antagonists: a real-world study based on post-marketing drug monitoring data.

Liver injury is the hallmark adverse reaction of endothelin receptor antagonist (ERA). Since the first drug, bosentan has been widely used in clinical practice, hepatotoxicity has been accompanied by the history of ERA. The new ERA has been proven to have a lower liver risk but the current research findings are inconsistent. ERA-based targeted drug combinations are commonly used in the treatment of pulmonary arterial hypertension, where the risk of liver injury is difficult to estimate. This study aimed to compare the correlation between ERA and different ERA combination regimens with liver injury in the real world. This is a retrospective study using data from the Adverse Event Reporting System (Food and Drug Administration AERS, FAERS). The study used proportional imbalance and Bayesian analysis to mine FAERS data from January 2004 to December 2022 to determine the association of three ERAs with liver injury and to further mine the risk of liver injury due to the combination of ERAs with other targeted drugs. In addition, we analyzed the onset time, mortality, and hospitalization rate of liver injury caused by different ERA combination regimens. We screened out 3581 ERA-related liver injury events, of which bosentan (59.82%) had the largest number of cases. The patients with liver injury were mainly female (60.63%), and the age was concentrated between 61 and 75 years (26.75%). According to different signal mining methods, reporting odds ratio (ROR; 3.38, 95% confidence interval = 3.23-3.53), proportional reporting ratio (PRR; 3.22, χ2 = 37.84), Bayesian confidence propagation neural network (BCPNN; 1.68, 95% confidence interval = 1.61), multi-item gamma Poisson shrinker (MGPS; 3.21, 95% confidence interval = 3.09), bosentan had the strongest association with liver injury compared to ambrisentan and macitentan. Furthermore, bosentan + sildenafil [ROR (2.52, 95% confidence interval = 2.23-2.84), PRR (2.44, χ2 = 15.92), BCPNN (1.29, 95% confidence interval = 1.14), MGPS (2.44, 95% confidence interval = 2.21)], bosentan + epoprostenol [ROR (5.39, 95% confidence interval = 4.29-6.77), PRR (4.94, χ2 = 65.18), BCPNN (2.30, 95% confidence interval = 1.83), MGPS (4.94, 95% confidence interval = 4.08)], bosentan + iloprost [ROR (2.70, 95% confidence interval = 2.11-3.45), PRR (2.61, χ2 = 31.03), BCPNN (1.38, 95% confidence interval = 1.08), MGPS (2.61, 95% confidence interval = 2.12)] had a higher risk of liver injury caused by the three ERA combination regimens. The median time to onset of hepatotoxicity associated with all ERA combination regimens was 259 days (interquartile range: 58-716.5 days). Finally, the hospitalization rate for patients experiencing hepatotoxicity with ERA combination regimens was 47.86% and the mortality rate was 12.67%. By mining the FAERS, we analyzed and compared the risk of liver injury related to different ERA and ERA combination regimens, and the onset time and adverse reaction outcomes of all ERA combination regimens. According to the results of the study, bosentan had the highest risk of liver injury and the combination regimens bosentan + sildenafil, bosentan + epoprostenol, and bosentan + iloprost had a stronger risk of liver injury. From the early stages of treatment, we need to regularly monitor the liver function of patients, especially for females and the elderly, and discontinue the suspected drug as soon as the liver injury occurs.

Updates on altered signaling pathways in tumor drug resistance

Curing cancer has always presented a formidable clinical challenge. Among the various treatment strategies for combating tumors, the combination of targeted therapy and immunotherapy has recently assumed significant importance. Regrettably, while targeted drugs demonstrate efficiency in the early stages of cancer treatment, patients inevitably develop drug resistance as treatment progresses, ultimately resulting in treatment failure and death. Currently, effective countermeasures against drug-resistant tumor cells remain limited, and research into the mechanisms of drug resistance continues to garner profound interest. The current understanding of drug resistance primarily focuses on two aspects: intrinsic or primary drug resistance, and acquired or secondary drug resistance. Further explanations delve into molecular mechanisms, including acquired gene mutations, epigenetic modifications, the plasticity of cancer stem cells, and the mediation of exosomes. With the advancement of single-cell analysis, our understanding of these potential mechanisms has become more comprehensive. In this review, we initially explore classical signaling pathways related to tumorigenesis and cancer cell progression. Additionally, we summarize recent findings regarding gene mutations and modifications related to drug resistance in cancer. Finally, we discuss the plasticity of cancer stem cells and the latest research on exosome-mediated tumor drug resistance.

Impact of Living Donor Liver Transplantation on the Improvement of Hepatocellular Carcinoma Treatment.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths, with increasing incidence. There are different treatment options, but only 30%-40% of HCC cases are diagnosed at an early stage for curative treatment. With the implementation of Milan Criteria for liver transplantation (LT) in HCC cases and its use for organ allocation with successful outcomes, LT has become an optimal treatment. Seeking new criteria for LT and developing updated algorithms for HCC treatment has become a hot topic nowadays. With the experience in living donor liver transplantation (LDLT), especially in Asian countries, LDLT was established and adopted with different criteria for HCC treatment, especially including criteria beyond Milan's size and number of tumors. Living donor grafts are uniquely different than deceased donor grafts as they are not considered a public resource. A living donor graft is rather a private gift intended for a specific recipient. Living donor livers are not limited by organ allocation systems, and this significant advantage of LDLT has opened new frontiers in the treatment of HCC. Improvements in LDLT have had remarkable parallel effects in the successful treatment of HCC as supported by a growing body of literature in the past decade.

A106: Aerobic Exercise Modulates GPCR/cAMP/PKA Signaling Pathway and Complement-Microglia Axis to Prevent Synaptic Loss in APP/PS1 Mice

Purpose: Synaptic failure serves as a primary contributor to memory dysfunction in Alzheimer's disease (AD). Physical exercise has demonstrated the potential to thwart and delay degenerative alterations in memory functions linked to AD. Investigating the underlying mechanisms may unveil crucial insights into early pathological changes, offering breakthroughs for both understanding and treating AD. Methods: We utilized 3-month-old APP/PS1 mice and subjected them to a 12-week aerobic exercise intervention. The spatial learning and memory functions of the mice were assessed using the Morris water maze test, while Golgi staining was employed to determine dendritic spine density in each mouse group. To analyze the potential mechanisms mediating the effects of exercise intervention in the AD brain, we conducted RNA sequencing. Subsequently, pathway enrichment analysis, immunofluorescence, real-time quantitative PCR, and western blotting were employed to elucidate the impact of regular aerobic exercise on the GPCR/cAMP/PKA signaling pathway and complement-microglia axis. Results: Our findings reveal that a 12-week aerobic exercise intervention significantly enhanced spatial learning and memory function in APP/PS1 mice. Moreover, it led to a substantial increase in dendritic spine density and elevated expression of postsynaptic density protein 95 (PSD-95) in the cortex and hippocampus. Aerobic exercise demonstrated the ability to improve the expression of certain genes and enhance synaptic pathways in the brains of APP/PS1 mice. This suggests that aerobic exercise facilitates synaptic growth in APP/PS1 mice by modulating G protein-coupled receptors (GPCRs) and activating the cAMP signaling pathway, with significant alterations observed in the expressions of Hcar1 and Vipr2 genes. Furthermore, exercise intervention resulted in the significant down-regulation (P < 0.05 or P < 0.01) of cAMP, p-PKA/PKA, GluA1, and CaMKII protein expressions in the brain tissue of APP/PS1 mice, which were subsequently up-regulated after exercise (P < 0.01). Notably, regular aerobic exercise effectively suppressed the activation of IBA-1+ microglia cells (P < 0.01), reversed changes in M1 phenotype markers (Cd86 and iNOS) and M2 phenotype markers (Arg-1) of microglia cells (P < 0.05), reduced the production of promoters C1q and central factor C3 in the macrosomatic cascade (P < 0.05), and prevented the colocalization of microglia and PSD-95 (P < 0.01). Conclusion: In conclusion, our results indicate that physical exercise plays a pivotal role in fostering early synaptic growth and averting synaptic loss in Alzheimer's disease (AD). This effect may be attributed to the regulation of the G protein-coupled receptors (GPCRs)/cAMP/PKA signaling pathway and the suppression of complement-mediated microglial phagocytosis of synapses. This mechanistic insight underscores the inherent contribution of exercise to health promotion, offering potential avenues for synaptic-focused interventions in the early stages of AD treatment.

The future is on the way: β cell function preservation for type 1 diabetes

This phase 3 trial of PROTECT confirms the beneficial effects of teplizumab (anti-CD3 treatment) in type 1 diabetes and expands the indications from diabetes prevention (stage 2) to early treatment (stage 3). More efforts are needed to confirm the effects in the general population, with a higher dose, and with repeated dosing.

Efficacy and safety of cervical conization combined with neoadjuvant chemotherapy versus radical trachelectomy in early-stage cervical cancer treatment

Efficacy and safety of cervical conization combined with neoadjuvant chemotherapy versus radical trachelectomy in early-stage cervical cancer treatment

Strategies for engineering oncolytic viruses to enhance cancer immunotherapy.

Non-small cell lung cancer (NSCLC) is the predominant form of lung cancer and is characterized by rapid metastasis and high mortality, presenting a challenge for early-stage treatment modalities. The heterogeneity of NSCLC's tumor microenvironment (TME) significantly influences the efficacy of anti-PD-1 immune checkpoint inhibitors (ICIs) therapy, leading to varied patient responses. This review characterized different strains of oncolytic viruses in NSCLC and the different gene edits in pre-existing oncolytic viruses. This study also aimed to provide strategies to enhance anti-PD-1 therapy in NSCLC by engineering oncolytic viruses (OVs). This study offers insights into the genomic adaptations necessary for OVs targeting NSCLC, identify genetic determinants of anti-PD-1 response variability, and propose genomic edits to bolster therapy effectiveness. The primary goal of this study is to present a theoretically designed OV with a detailed genomic framework capable of enhancing the response to anti-PD-1 therapy, thereby advancing the field of cancer immunotherapy.

PSMA-targeted dendrimer as an efficient anticancer drug delivery vehicle for prostate cancer.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in the United States. Although early-stage treatments exhibit promising 5-year survival rates, the treatment options for advanced stage disease are constrained, with short survival benefits due to the challenges associated with effective and selective drug delivery to PCa cells. Even though targeting Prostate Specific Membrane Antigen (PSMA) has been extensively explored and is clinically employed for imaging and radio-ligand therapy, the clinical success of PSMA-based approaches for targeted delivery of chemotherapies remains elusive. In this study, we combine a generation 4 hydroxy polyamidoamine dendrimer (PD) with irreversible PSMA ligand (CTT1298) to develop a PSMA-targeted nanoplatform (PD-CTT1298) for selective intracellular delivery of potent chemotherapeutics to PCa. PD-CTT1298-Cy5 exhibits a PSMA IC50 in the nanomolar range and demonstrates selective uptake in PSMA (+) PCa cells via PSMA mediated internalization. When systemically administered in a prostate tumor xenograft mouse model, PD-CTT1298-Cy5 selectively targets PSMA (+) tumors with significantly less accumulation in PSMA (-) tumors or upon blocking of the PSMA receptors. Moreover, the dendrimer clears rapidly from the off-target organs limiting systemic side-effects. Further, the conjugation of an anti-cancer agent, cabozantinib to the PSMA-targeted dendrimer translates to a significantly enhanced anti-proliferative activity in vitro compared to the free drug. These findings highlight the potential of PD-CTT1298 nanoplatform as a versatile approach for selective delivery of high payloads of potent chemotherapeutics to PCa, where dose related systemic side-effects are a major concern.

Integrating Psychotherapeutic Interventions for Enhanced Resilience and Coping in a Cancer Patient: A Case Study

Cancer, a formidable adversary of human health and well-being, imposes profound physical and emotional challenges upon those who are diagnosed with it. This case study embarks on an exploration into the transformative potential of psychotherapeutic interventions in a 49-year-old female who had been diagnosed with clear cell carcinoma of the left ovary. Psychotherapeutic interventions were systematically integrated into the early stages of cancer treatment. The structured psychotherapeutic interventions consisted of client-centered counselling coupled with mindfulness training and cognitive restructuring. The aim of the intervention was to provide more comprehensive and effective paradigm in cancer care. A mixed-method approach, combining qualitative and quantitative assessment using Brief-COPE scale and Brief Resilience scale was employed. Findings indicated a marked improvement in the patient's resilience, coping, and capacity to confront the physical and emotional challenges posed by cancer. The novel aspect of this research lies in its meticulous examination of a single patient's journey, showcasing the potential of a highly individualized approach.

Relationship of imipenem therapeutic drug monitoring to clinical outcomes in critically ill patients: a retrospective cohort study.

The primary objective of this study was to evaluate the predictors associated with target concentration (non-)attainment of imipenem in critically ill patients. The secondary objective was to explore the correlation between achieving imipenem target concentrations and clinical outcomes of therapy. A retrospective cohort study was conducted in critically ill patients treated with imipenem. Clinical data were extracted from the patients' electronic medical records. The pharmacokinetic/pharmacodynamic target was defined as free imipenem concentrations above the minimum inhibitory concentration (MIC) of the pathogen at 100% (100%fT>MIC) of the dosing interval. Factors associated with the non-attainment of target concentrations were evaluated using binomial logistic regression. Kaplan-Meier analysis was used to investigate the correlation between (non-)attainment targets and 30-day mortality. A total of 406 patients were included, and 55.4% achieved the target of 100%fT>MIC. Regression analysis identified an initial daily dose of imipenem ≤ 2 g/day, augmented renal clearance, age ≤ 60 years, recent surgery, and absence of positive microbiology culture as risk factors for target non-attainment. Achieving the 100%fT>MIC target was significantly associated with clinical efficacy but not with 30-day mortality. Selective application of therapeutic drug monitoring in the early stages of imipenem treatment for critically ill patients can improve clinical outcomes. Further research should explore the potential benefits of TDM-guided dosing strategies for imipenem in critical care settings.