The combination of immune checkpoint inhibitors and antibody-drug conjugates in the treatment of urogenital tumors: a review insights from phase 2 and 3 studies.

With the high incidence of urogenital tumors worldwide, urinary system tumors are among the top 10 most common tumors in men, with prostate cancer ranking first and bladder cancer fourth. Patients with resistant urogenital tumors often have poor prognosis. In recent years, researchers have discovered numerous specific cancer antigens, which has led to the development of several new anti-cancer drugs. Using protein analysis techniques, researchers developed immune checkpoint inhibitors (ICIs) and antibody-conjugated drugs (ADCs) for the treatment of advanced urogenital tumors. However, tumor resistance often leads to the failure of monotherapy. Therefore, clinical trials of the combination of ICIs and ADCs have been carried out in numerous centers around the world. This article reviewed phase 2 and 3 clinical studies of ICIs, ADCs, and their combination in the treatment of urogenital tumors to highlight safe and effective methods for selecting individualized therapeutic strategies for patients. ICIs activate the immune system, whereas ADCs link monoclonal antibodies to toxins, which can achieve a synergistic effect when the two drugs are combined. This synergistic effect provides multiple advantages for the treatment of urogenital tumors.

Molecular understanding and clinical outcomes of CAR T cell therapy in the treatment of urological tumors.

Chimeric antigen receptor engineered T (CAR T) cell therapy has developed rapidly in recent years, leading to profound developments in oncology, especially for hematologic malignancies. However, given the pressure of immunosuppressive tumor microenvironments, antigen escape, and diverse other factors, its application in solid tumors is less developed. Urinary system tumors are relatively common, accounting for approximately 24% of all new cancers in the United States. CAR T cells have great potential for urinary system tumors. This review summarizes the latest developments of CAR T cell therapy in urinary system tumors, including kidney cancer, bladder cancer, and prostate cancer, and also outlines the various CAR T cell generations and their pathways and targets that have been developed thus far. Finally, the current advantages, problems, and side effects of CAR T cell therapy are discussed in depth, and potential future developments are proposed in view of current shortcomings.

The relationship between the network of non-coding RNAs-molecular targets and N6-methyladenosine modification in tumors of urinary system.

N6-methyladenosine (m6A) methylation, a prevalent eukaryotic post-transcriptional modification, is involved in multiple biological functions, including mediating variable splicing, RNA maturation, transcription, and nuclear export, and also is vital for regulating RNA translation, stability, and cytoplasmic degradation. For example, m6A methylation can regulate pre-miRNA expression by affecting both splicing and maturation. Non-coding RNA (ncRNA), which includes microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), does not encode proteins but has powerful impacts on transcription and translation. Conversely, ncRNAs may impact m6A methylation by affecting the expression of m6A regulators, including miRNAs targeting mRNA of m6A regulators, or lncRNAs, and circRNAs, acting as scaffolds to regulate transcription of m6A regulatory factors. Dysregulation of m6A methylation is common in urinary tumors, and the regulatory role of ncRNAs is also important for these malignancies. This article provides a systematic review of the role and mechanisms of action of m6A methylation and ncRNAs in urinary tumors.

Knowledge mapping and current trends of m6A methylation in the field of cancer.

Background: Cancer is a serious threat to people's lives and health, killing millions of people every year. Here, we performed a bibliometric analysis of tumor N6-methyladenosine methylation data between 2001 and 2022 to understand research trends and potential future directions. Methods: A total of 890 papers published in the Web of Science core collection database between January 1, 2001 and December 31, 2022 were analyzed. Bibliometric analysis was performed using VOSviewer software to explore citations, co-authorship, co-citations, and co-occurrence. Results: Although few papers were published before 2018, there was a rapid increase in publications after 2018. The People's Republic of China published 810 papers with 16,957 citations, both ranking first in the word. Sun Yat Sen University had the highest number of citations and published articles (67 published papers and 2702 citations), indicative of its active collaborative research status. Wang Xiao was the most co-cited author with 546 co-citations. Huang Yufei and Meng Jia ranked first with a link strength of 22, making them the most active collaborative authors. Frontiers in Oncology and Nature were the most active and co-cited journals, with 57 papers and 1953 co-citations, respectively. Studies of tumor N6-methyladenosine methylation can be divided into three categories: "tumor metabolism", "tumor bioinformatics and immunity", and "tumor progression". Conclusions: This study systematically summarized the research on tumor N6-methyladenosine methylation during the past 20 years and suggested potential ways to explore its biomarkers and immunotherapy in the future.

Emerging strategy for the treatment of urothelial carcinoma: Advances in antibody-drug conjugates combination therapy.

Urothelial carcinoma (UC) is a prevalent malignant tumor involving the urinary system. Although there are various treatment modalities, including surgery, chemotherapy, and immune checkpoint inhibitor (ICI) therapy, some patients experience disease recurrence and metastasis with poor prognosis and dismal long-term survival. Antibody-drug conjugates (ADCs), which combine the targeting ability of antibody drugs with the cytotoxicity of chemotherapeutic drugs, have recently emerged as a prominent research focus in the development of individualized precision cancer therapy. Although ADCs have improved the overall response rate in patients with UC, their effectiveness remains limited. Currently, ADC-based combination therapies, particularly ADC combined with ICIs, have demonstrated promising efficacy. This combination approach has advanced the treatment of UC, exhibiting the potential to become the standard first-line therapy for advanced UC in the future. This article reviewed clinical trials involving ADC-based combination therapy for UC and discussed the possible challenges and future perspectives to provide guidance for the clinical treatment of UC.

Serotonin syndrome caused by a CYP2C19-mediated interaction between low-dose escitalopram and clopidogrel: a case report.

Background: Serotonin syndrome has been recognized as a serious adverse reaction to antidepressants and is characterized by sudden or severe autonomic nerve dysfunction and neuromuscular symptoms. Without an accurate diagnosis and prompt treatment, serotonin syndrome progresses rapidly and can be life-threatening. It is usually related to the dose of 5-hydroxytryptamine drugs, and the dose is the basis for diagnosis. Therefore, serotonin syndrome induced by low-dose antidepressants rarely occurs, and clinicians are more likely to misdiagnose patients who take low-dose antidepressants with similar symptoms. Here, we present a case study of serotonin syndrome caused by a relatively low dose of escitalopram, which is not common in past references. Case summary: The patient was a 74-year-old Asian woman with a 42-year history of schizophrenia. After 6 weeks of antidepressant treatment, our patient presented with characteristic myoclonus in the lower limbs and closed eyes with fluttering. Initially, she was misdiagnosed with neuroleptic malignant syndrome (NMS) due to antipsychotic medication and was treated accordingly, even with discontinuation of clozapine. However, her symptoms persisted, and then therapeutic drug monitoring was initiated with the involvement of a clinical pharmacist. Eventually, she was diagnosed with serotonin syndrome due to escitalopram levels reaching the warning level. Subsequently, the patient's treatment was modified, and her clinical outcome was satisfactory without any other serious adverse reactions. Gene detection was also performed, and a cytochrome P450 enzyme (CYP) 2C19-mediated interaction between low-dose escitalopram and clopidogrel seems to be a possible mechanism. Conclusion: Data on this is extremely scarce, and to the best of our knowledge, serotonin syndrome caused by low-dose antidepressants has not yet been discussed to any great extent in the literature. Our case provides more clinical experience in the treatment of serotonin syndrome.

A review of current evidence about lncRNA MEG3: A tumor suppressor in multiple cancers.

Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) is a lncRNA located at the DLK1-MEG3 site of human chromosome 14q32.3. The expression of MEG3 in various tumors is substantially lower than that in normal adjacent tissues, and deletion of MEG3 expression is involved in the occurrence of many tumors. The high expression of MEG3 could inhibit the occurrence and development of tumors through several mechanisms, which has become a research hotspot in recent years. As a member of tumor suppressor lncRNAs, MEG3 is expected to be a new target for tumor diagnosis and treatment. This review discusses the molecular mechanisms of MEG3 in different tumors and future challenges for the diagnosis and treatment of cancers through MEG3.

lncRNA PVT1: a novel oncogene in multiple cancers.

Long noncoding RNAs are involved in epigenetic gene modification, including binding to the chromatin rearrangement complex in pre-transcriptional regulation and to gene promoters in gene expression regulation, as well as acting as microRNA sponges to control messenger RNA levels in post-transcriptional regulation. An increasing number of studies have found that long noncoding RNA plasmacytoma variant translocation 1 (PVT1) plays an important role in cancer development. In this review of a large number of studies on PVT1, we found that PVT1 is closely related to tumor onset, proliferation, invasion, epithelial-mesenchymal transformation, and apoptosis, as well as poor prognosis and radiotherapy and chemotherapy resistance in some cancers. This review comprehensively describes PVT1 expression in various cancers and presents novel approaches to the diagnosis and treatment of cancer.

Functions and underlying mechanisms of lncRNA HOTAIR in cancer chemotherapy resistance.

Chemotherapy has been one of the most important treatments for advanced cancer in recent decades. Although the sensitivity rate of initial chemotherapy is high, patients with chemotherapy resistant tumors, experience tumor recurrence. In recent years, many studies have shown that homeobox transcript antisense intergenic RNA (HOTAIR) is involved in many pathological processes including carcinogenesis. The abnormal regulation of a variety of cell functions by HOTAIR, such as apoptosis, the cell cycle, epithelial-mesenchymal transition, autophagy, self-renewal, and metabolism, is associated with chemotherapy resistance. Therefore, there is an urgent need to understand the biology and mechanism underlying the role of HOTAIR in tumor behavior and its potential as a biomarker for predicting the effect of chemotherapy. In this manuscript, we review the mechanisms underlying HOTAIR-related drug resistance and discuss the limitations of current knowledge and propose potential future directions.

The global status of research in prostate cancer bone metastasis: A bibliometric and visualized analysis.

Background: Prostate cancer (PCa) is a serious threat to the health of elderly aged groups. It is very important to understand the occurrence and development of PCa for early diagnosis, treatment and metastasis control. This study aims to elucidate the international frontier research direction and literature distribution through bibliometric and visual analyses of PCa bone metastasis. Methods: Data were obtained from the Web of Science core collection database, which collected 2,246 papers related to PCa bone metastasis from 1 January 2012 to 31 December 2021. The collected data were analyzed using the VOSviewer software for citation, co-authorship, co-citation, bibliometric coupling, and co-occurrence. Results: Over the past decade, published papers have increased annually. The United States of America has published 890 papers with 29,161 citations, far more than any other country, and it has the most extensive collaboration with other countries. For example, 33 articles by Saad Fred were cited 2,721 times, and 91 articles from the University of Texas MD Anderson CANC CTR were cited 3,037 times, the most cited author and organization. Peng Xinsheng and Duke UNIV comprise the most active collaborative author and organization, respectively. The most co-cited journal was CANCER RES, with 3,195 citations. Studies of PCa bone metastasis can be divided into four categories: "basic research," "auxiliary diagnosis and treatment," "clinical trial," and "prognosis." Conclusion: Our results provide a comprehensive overview of the research priorities and future directions of PCa bone metastasis, which can further accurately guide researchers in diagnosis, treatment, and personalized prevention.

On the Quasi-Three Dimensional Configuration of Magnetic Clouds.

We develop an optimization approach to model the magnetic field configuration of magnetic clouds, based on a linear force-free formulation in three dimensions. Such a solution, dubbed the Freidberg solution, is kin to the axisymmetric Lundquist solution, but with more general "helical symmetry." The merit of our approach is demonstrated via its application to two case studies of in situ measured magnetic clouds. Both yield results of reduced χ 2 ≈ 1. Case 1 shows a winding flux rope configuration with one major polarity. Case 2 exhibits a double-helix configuration with two flux bundles winding around each other and rooted on regions of mixed polarities. This study demonstrates the three-dimensional complexity of the magnetic cloud structures.

Predicting the risk of cardiac myxoma in Carney complex.

PURPOSE: Carney complex (CNC), is an autosomal dominant multiple neoplasia and lentiginosis syndrome. We aimed to identify risk factors associated with the occurrence and recurrence of cardiac myxomas, the predominant cause of death in CNC patients. METHODS: Patients with CNC were monitored prospectively between 1995 and 2020 for the development of cardiac myxomas. RESULTS: Of the 319 patients studied, 136 (42.6%) developed myxomas. The mean age at diagnosis was 28.7 ± 16.6 years in females and 25.0 ± 16.4 years in males. By age 30, 35% of females and 45% of males had at least one myxoma. The CNC-related lesions, lentigines, cutaneous, mucosal, or breast myxomas, thyroid nodules, pituitary adenoma, and schwannoma were significantly more frequent (all p < 0.05) among patients with myxomas. Forty-four percent of patients had recurrences; nearly all within the first 8 and 16 years for males and females, respectively. Recurrences were more common in females. CONCLUSION: This is the largest study to date and provides the first-time risk estimates by age and gender for cardiac myxomas in CNC patients. Cardiac myxomas are common by age 30 and often recur, especially in women, but the risk drops in 10 to 20 years. These findings may guide patient counseling, screening intervals, and surgical approaches. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration: Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease and the Carney complex, Registration number: NCT00001452 URL: https://clinicaltrials.gov/ct2/show/NCT00001452.

Metagenomics Reveal Correlations Between Microbial Organisms in Soils and the Health of Populus euphratica.

Biological diversity plays an important role in the stability of ecosystems. The Mu Us Desert (MUD), located in Northern China, is an aeolian desert. Although it has been governed by a series of ecological restoration programs, the MUD still has limited biological diversity. Populus euphratica (P. euphratica), a xerophytic plant, has great potential to improve the biological diversity of the MUD. However, the survival rate of P. euphratica in the MUD has been very low. The current study tried to explore the mechanism of the high death rate of P. euphratica in the microbiome perspective. The correlation study between soil community composition and soil properties showed that water-filled pore space (WFPS), pH, EC, AP, NO3 -, and NH4 + possess higher potential to change the bacterial community (18%) than the fungal community (9%). Principal coordinate analysis indicated that the composition of both bacteria (Proteobacteria and Bacteroidetes) and fungi (Ascomycota) in the root soil can be increased by P. euphratica. By systematically comparing between the fungal diversity in the root soil around P. euphratica and the pathogenic fungus extract from the pathogenic site of P. euphratica, we found that the high death rate of P. euphratica was associated with specific pathogenic fungus Alternaria alternate and Didymella glomerata. In addition, the microbiome composition analysis indicated that P. euphratica planting could also influence the portions of bacteria community, which also has great potential to lead to future infection. However, as the extraction and separation of bacteria from plants is challenging, the correlation between pathogenic bacteria and the high death rate of P. euphratica was not studied here and could be explored in future work.

Crash rates over time among younger and older drivers in the SHRP 2 naturalistic driving study.

OBJECTIVE: To examine crash rates over time among 16-17-year-old drivers compared to older drivers. METHODS: Data were from a random sample of 854 of the 3,500 study participants in SHRP 2, a U.S. national, naturalistic driving (instrumented vehicle) study. Crashes/10,000 miles by driver age group, 3-month period, and sex were examined within generalized linear mixed models. RESULTS: Analyses of individual differences between age cohorts indicated higher incidence rates in the 16-17-year old cohort relative to older age groups each of the first four quarters (except the first quarter compared to 18-20 year old drivers) with incident rate ratios (IRR) ranging from 1.98 to 18.90, and for the full study period compared with drivers 18-20 (IRR = 1.69, CI = 1.00, 2.86), 21 to 25 (IRR = 2.27, CI = 1.31, 3.91), and 35 to 55 (IRR = 4.00, CI = 2.28, 7.03). Within the 16-17-year old cohort no differences were found in rates among males and females and the decline in rates over the 24-month study period was not significant. CONCLUSIONS: The prolonged period of elevated crash rates suggests the need to enhance novice young driver prevention approaches such as Graduated Driver's Licensing limits, parent restrictions, and post-licensure supervision and monitoring. Practical Applications: Increases are needed in Graduated Driver's Licensing limits, parent restrictions, and postlicensure supervision and monitoring.

Learner Driver Experience and Teenagers' Crash Risk During the First Year of Independent Driving.

Importance: One mechanism for teenagers' elevated crash risk during independent driving may be inadequate learner driving experience. Objective: To determine how learner driver experience was associated with crash risk during the first year of independent driving. Design, Setting, and Participants: Youth aged 15.5 to 16.1 years at recruitment were eligible to participate. Participants' vehicles were instrumented with sensors, and driving was recorded during the learner period through 1 year of independent driving. Data were collected from January 2011 through August 2014 in southwestern Virginia. Exposures: The amount, consistency and variety of practice, driving errors, and kinematic risky driving (KRD) rates during the learner period were recorded. Surveys, including one on sensation-seeking personality traits, were assessed at baseline. Main Outcomes and Measures: Cox proportional hazard regressions examined associations between individual characteristics and learner driving experience with driving time to first crash and all crashes in the first year of independent driving. So that hazard ratios (HRs) can be directly comparable, units of measurement were standardized to the interquartile range. Results: Of 298 individuals who responded to recruitment, 90 fulfilled the criteria and 82 completed the study (of whom 75 were white [91%] and 44 were girls [54%]). Teenage participants drove a mean (SD) of 1259.2 (939.7) miles over 89 days during the learner period. There were 49 property-damage crashes and/or police-reportable crashes during independent driving. Factors associated with driving time to first crash included higher sensation-seeking personality scale scores (HR, 1.67 [95% CI, 1.08-2.57] per 0.75-unit increase), learner driving KRD rates (HR, 1.27 [95% CI, 1.12-1.43] per 9.24-unit increase), and learner driving errors (HR, 0.44 [95% CI, 0.22-0.86] per increase of 6.48 errors). Similar results were obtained for all crashes in the first year, with the addition of consistency of learner driving practice (HR, 0.61 [95% CI, 0.38-0.99] per 0.23-unit increase). Conclusions and Relevance: Individual characteristics and learner driving experiences were associated with crash risk during independent driving. As expected, there was an association between sensation seeking and crashes. Elevated KRD rates during the learner period may reflect risky driving behavior among novices or tolerance to abrupt maneuvers by parents who supervise driving. Consistent practice throughout the learner period could reduce teenage crash risk, which is supported by learning theories indicating distributed practice is effective for developing expertise. Errors during practice may constitute learning events that reinforce safer driving. Physicians could encourage parents to provide opportunities for regular practice driving and monitor their teenager's KRD rates during the learner period using in-vehicle or smartphone-based technology.

Kinematic risky driving behavior among younger and older drivers: Differences over time by age group and sex.

Objective: This research examined the incidence rates of elevated gravitational force events (kinematic risky driving, KRD) among 16- to 17-year-old drivers compared to those of 18- to 20-year-old, 21- to 25-year-old, and 35- to 55-year-old drivers over a 12-month period. Methods: Data were sampled from the Strategic Highway Research Program 2 (SHRP2) naturalistic driving study that recruited a U.S. national sample of study participants. General linear mixed models (GLIMMIX) for recurrent events were used to estimate KRD incident rates for age cohorts in 3-month periods. Results: KRD incidence rates for 16- to 17-year-old drivers were higher than the rates for older drivers at each 3-month period. Analyses of individual differences for the 12-month period indicated that incidence rates for the 16- to 17-year-old group were 1.84 times higher than the rates for 18- to 20-year-old drivers, 2.86 higher than those for 21- to 25-year-old drivers, and 4.92 times higher than those for 35- to 55-year-old drivers. The incident rate for 16- to 17-year-old males was 1.9 times higher than that for same-aged females in the first 3 months and 2.3 times higher over 12 months. Over the study period, KRD rates of 16- to 17-year-old participants declined 24.5% among females and 18.0% among males. Conclusions: KRD rates were higher among younger relative to older, more experienced drivers and did not decline over time, consistent with a protracted period of risky driving behavior. The persistently higher KRD rate among young drivers suggests the need to enhance crash prevention approaches, such as feedback about abrupt maneuvering, to young drivers and their parents.

Maternal and Offspring Genetic Risk of Type 2 Diabetes and Offspring Birthweight Among African Ancestry Populations.

OBJECTIVES: Maternal genetic risk of type 2 diabetes (T2D) can influence offspring birthweight through shared offspring genetic risk and by altering intrauterine glycemic status. The aim of this study was to estimate the independent effects of maternal and offspring genetic risk scores (GRSs) of T2D on offspring birthweight and the extent to which intrauterine glycemic traits mediate the effect of maternal GRSs on offspring birthweight. DESIGN: The study involved 949 mother-offspring pairs of African ancestry from the Hyperglycemia Adverse Pregnancy Outcome study. GRSs of T2D were calculated separately for mothers and offspring as the weighted sum of 91 T2D risk alleles identified in a genome-wide association study meta-analysis in African Americans. Linear regression models were fit to estimate changes in birthweight by quartiles of GRSs. Mediation analysis was implemented to estimate the direct and indirect effects of maternal GRS on offspring birthweight through cord blood C-peptide and maternal fasting and postchallenge glucose levels. RESULTS: Maternal and offspring GRSs were independently and differentially associated with offspring birthweight. Changes (95% CI) in birthweight across increasing quartiles of maternal GRSs were 0 g (reference), 83.1 g (6.5, 159.6), 103.1 g (26.0, 180.2), and 92.7 g (12.6, 172.8) (P trend = 0.041) and those of offspring GRSs were 0 (reference), -92.0 g (-169.2, -14.9), -64.9 g (-142.4, 12.6), and 2.0 g (-77.8, 81.7) (P trend = 0.032). Cord blood C-peptide mediated the effect of maternal GRS on offspring birthweight, whereas maternal postchallenge glucose levels showed additive effects with maternal GRS on birthweight. CONCLUSIONS: Maternal and offspring GRSs of T2D were independently and differentially associated with offspring birthweight.

The Effect of Teenage Passengers on Simulated Risky Driving Among Teenagers: A Randomized Trial.

Teenage passengers might influence risky driving, particularly in certain mental states. Notably, social exclusion could increase social conformity. Two studies examined simulated intersection management among young drivers after a social exclusion activity (Cyberball). In Study 1 [112 males (mean = 17.3 years)], risky driving was significantly greater among excluded males driving with a risk-accepting vs. passive passenger; no effect of social exclusion. In Study 2 [115 females (mean = 17.1 years)], risky driving was significantly greater among excluded females driving with a risk-accepting vs. a passive passenger, and greater among those included (fair play) vs. excluded when driving with a risk-accepting passenger. Risky driving behavior among male and female teenagers may be influenced uniquely by passenger norms and social exclusion.

Altered expression of the CSMD1 gene in the peripheral blood of schizophrenia patients.

BACKGROUND: Schizophrenia (SCZ) is a heritable, refractory, and devastating psychiatric disorder. Previous studies have shown that the variants of CUB and sushi multiple domains 1 (CSMD1) demonstrate significant genome-wide association with SCZ. However, few studies have been conducted on the effect of antipsychotics on the expression levels of CSMD1. This study explored whether a change occurs in the expression of the CSMD1 gene before and after antipsychotic treatment in SCZ patients. METHODS: The study population comprised Han Chinese patients from eastern China, including 32 SCZ patients and 48 healthy controls. The expression of CSMD1 before and after treatment in the SCZ group and between the two groups was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: The expression levels of the CSMD1 gene in the peripheral blood mononuclear cells (PBMCs) of SCZ patients were lower than those in the healthy controls. The expression levels of the CSMD1 gene in the PBMCs of the SCZ patients after antipsychotic treatment were higher than those in the baseline SCZ patients (all P <  0.05). CONCLUSIONS: Our results showed that the expression levels of CSMD1 are correlated with the development and treatment of SCZ, providing further evidence for the involvement of CSMD1 in SCZ.