Clinical-proteomic classification and precision treatment strategy of chordoma.

Chordoma is a rare and heterogeneous mesenchymal malignancy, with distinct clinical and biological behaviors. Till now, its comprehensive clinical-molecular characteristics and accurate molecular classification remain obscure. In this research, we enroll 102 patients with chordoma and describe their clinical, imageological, and histopathological features. Through tandem mass tag-based proteomic analysis and nonnegative matrix factorization clustering, we classify chordoma into three molecular subtypes: bone microenvironment-dominant, mesenchymal-derived, and mesenchymal-to-epithelial transition-mediated pattern. The three subtypes exhibit discrete clinical prognosis and distinct biological attributes of osteoclastogenesis and immunogenicity, oxidative phosphorylation, and receptor tyrosine kinase activation, suggesting targeted therapeutic strategies of denosumab, S-Gboxin, and anlotinib, respectively. Notably, these approaches demonstrate positive treatment outcomes for each subtype in vitro and in vivo. Altogether, this work sheds light on the clinical-proteomic characteristics of chordoma and provides a candidate precision treatment strategy for chordoma according to molecular classification, underscoring their potential for clinical application.

Unravelling the interplay between ER stress, UPR and the cGAS-STING pathway: Implications for osteoarthritis pathogenesis and treatment strategy.

Osteoarthritis (OA) is a debilitating chronic degenerative disease affecting the whole joint organ leading to pain and disability. Cellular stress and injuries trigger inflammation and the onset of pathophysiological changes ensue after irreparable damage and inability to resolve inflammation, impeding the completion of the healing process. Extracellular matrix (ECM) degradation leads to dysregulated joint tissue metabolism. The reparative effort induces the proliferation of hypertrophic chondrocytes and matrix protein synthesis. Aberrant protein synthesis leads to endoplasmic reticulum (ER) stress and chondrocyte apoptosis with consequent cartilage matrix loss. These events in a vicious cycle perpetuate inflammation, hindering the restoration of normal tissue homeostasis. Recent evidence suggests that inflammatory responses and chondrocyte apoptosis could be caused by the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling axis in response to DNA damage. It has been reported that there is a crosstalk between ER stress and cGAS-STING signalling in cellular senescence and other diseases. Based on recent evidence, this review discusses the role of ER stress, Unfolded Protein Response (UPR) and cGAS-STING pathway in mediating inflammatory responses in OA.

The role of JNK signaling pathway in organ fibrosis.

BACKGROUND: Fibrosis is a tissue damage repair response caused by multiple pathogenic factors which could occur in almost every apparatus and leading to the tissue structure damage, physiological abnormality, and even organ failure until death. Up to now, there is still no specific drugs or strategies can effectively block or changeover tissue fibrosis. JNKs, a subset of mitogen-activated protein kinases (MAPK), have been reported that participates in various biological processes, such as genetic expression, DNA damage, and cell activation/proliferation/death pathways. Increasing studies indicated that abnormal regulation of JNK signal pathway has strongly associated with tissue fibrosis. AIM OF REVIEW: This review designed to sum up the molecular mechanism progresses in the role of JNK signal pathway in organ fibrosis, hoping to provide a novel therapy strategy to tackle tissue fibrosis. KEY SCIENTIFIC CONCEPTS OF REVIEW: Recent evidence shows that JNK signaling pathway could modulates inflammation, immunoreaction, oxidative stress and Multiple cell biological functions in organ fibrosis. Therefore, targeting the JNK pathway may be a useful strategy in cure fibrosis.

Making the most out of timeseries symptom data: A machine learning study on symptom predictions of internet-based CBT.

Objective: Predicting who will not benefit enough from Internet-Based Cognitive Behavioral (ICBT) Therapy early on can assist in better allocation of limited mental health care resources. Repeated measures of symptoms during treatment is the strongest predictor of outcome, and we want to investigate if methods that explicitly account for time-dependency are superior to methods that do not, with data from (a) only two pre-treatment timepoints and (b) the pre-treatment timepoints and three timepoints during initial treatment. Methods: We use 1) commonly used time-independent methods (i.e., Linear Regression and Random Forest models) and 2) time-dependent methods (i.e., multilevel model regression, mixed-effects random forest, and a Long Short-Term Memory model) to predict symptoms during treatment, including the final outcome. This is done with symptom scores from 6436 ICBT patients from regular care, using robust multiple imputation and nested cross-validation methods. Results: The models had a 14 %-12 % root mean squared error (RMSE) in predicting the post-treatment outcome, corresponding to a balanced accuracy of 67-74 %. Time-dependent models did not have higher accuracies. Using data for the initial treatment period (b) instead of only from before treatment (a) increased prediction results by 1.3 % percentage points (12 % to 10.7 %) RMSE and 6 % percentage points BACC (69 % to 75 %). Conclusion: Training prediction models on only symptom scores of the first few weeks is a promising avenue for symptom predictions in treatment, regardless of which model is used. Further research is necessary to better understand the interaction between model complexity, dataset length and width, and the prediction tasks at hand.

The multifaceted effects of mitochondria in kidney diseases.

Mitochondria serve as the primary site for aerobic respiration within cells, playing a crucial role in maintaining cellular homeostasis. To maintain homeostasis and meet the diverse demands of the cells, mitochondria have evolved intricate systems of quality control, mainly including mitochondrial dynamics, mitochondrial autophagy (mitophagy) and mitochondrial biogenesis. The kidney, characterized by its high energy requirements, is particularly abundant in mitochondria. Interestingly, the mitochondria display complex behaviors and functions. When the kidney is suffered from obstructive, ischemic, hypoxic, oxidative, or metabolic insults, the dysfunctional mitochondrial derived from the defects in the mitochondrial quality control system contribute to cellular inflammation, cellular senescence, and cell death, posing a threat to the kidney. However, in addition to causing injury to the kidney in several cases, mitochondria also exhibit protective effect on the kidney. In recent years, accumulating evidence indicated that mitochondria play a crucial role in adaptive repair following kidney diseases caused by various etiologies. In this article, we comprehensively reviewed the current understanding about the multifaceted effects of mitochondria on kidney diseases and their therapeutic potential.

Synthetic lumbar MRI can aid in diagnosis and treatment strategies based on self-pix networks.

CT and MR tools are commonly used to diagnose lumbar fractures (LF). However, numerous limitations have been found in practice. The aims of this study were to innovate and develop a spinal disease-specific neural network and to evaluate whether synthetic MRI of the LF affected clinical diagnosis and treatment strategies. A total of 675 LF patients who met the inclusion and exclusion criteria were included in the study. For each participant, two mid-sagittal CT and T2-weighted MR images were selected; 1350 pairs of LF images were also included. A new Self-pix based on Pix2pix and Self-Attention was constructed. A total of 1350 pairs of CT and MR images, which were randomly divided into a training group (1147 pairs) and a test group (203 pairs), were fed into Pix2pix and Self-pix. The quantitative evaluation included PSNR and SSIM (PSNR1 and SSIM1: real MR images and Pix2pix-generated MR images; PSNR2 and SSIM2: real MR images and Self-pix-generated MR images). The qualitative evaluation, including accurate diagnosis of acute fractures and accurate selection of treatment strategies based on Self-pix-generated MRI, was performed by three spine surgeons. In the LF group, PSNR1 and PSNR2 were 10.884 and 11.021 (p < 0.001), and SSIM1 and SSIM2 were 0.766 and 0.771 (p < 0.001), respectively. In the ROI group, PSNR1 and PSNR2 were 12.350 and 12.670 (p = 0.004), and SSIM1 and SSIM2 were 0.816 and 0.832 (p = 0.005), respectively. According to the qualitative evaluation, Self-pix-generated MRI showed no significant difference from real MRI in identifying acute fractures (p = 0.689), with a good sensitivity of 84.36% and specificity of 96.65%. No difference in treatment strategy was found between the Self-pix-generated MRI group and the real MRI group (p = 0.135). In this study, a disease-specific GAN named Self-pix was developed, which demonstrated better image generation performance compared to traditional GAN. The spine surgeon could accurately diagnose LF and select treatment strategies based on Self-pix-generated T2 MR images.

Standardized treatment of oral cancer under the guidance of clinical practice guidelines of National Comprehensive Cancer Network.

Oral cancer represents a serious public health problem affecting oral and system health with a high global incidence. Treatment strategies for oral cancer vary in different disciplines and are likely to be limited to certain doctor's personal experience. While clinical practice guidelines are considered to enable doctors to determine the most appropriate and consistent treatment strategy according to the patient's situation. National Comprehensive Cancer Network (NCCN) clinical practice guidelines have become the most prevalent in global clinical oncology practice. This article mainly focuses on cases to discuss the normalized treatment strategy for oral cancer in different stages based on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Head and Neck Cancers, Version 3, 2024.

Cerebral abscess in Down syndrome: a systematic review on treatment and prognosis. Illustrative case.

BACKGROUND: No universal protocol exists for treating cerebral abscesses in Down syndrome. An illustrative case supplemented with a systematic literature review on brain abscesses in Down syndrome is presented, comprising a total of 16 cases. Preoperative infectious disease workups, cardiac examinations including echocardiography, as well as reported surgical and antibiotic treatments were correlated in the reported cohorts. OBSERVATIONS: Overall, 18.8% of cases (n = 3) had no reported cardiac evaluation. The majority of cases were treated surgically (n = 8), with aspiration (n = 3), drainage (n = 2), or other operations (n = 3); 25% (n = 4) were treated with antibiotics only. Strikingly, 25% of cases (n = 4) reported neither surgical nor antibiotic therapy, a significantly higher rate compared to 0%-3% of patients with brain abscess in other reported cohorts. Half of the patients (n = 8) who died either lacked a cardiac evaluation or had existing heart conditions. This mortality rate was about 4 times higher than the rates observed in other studies. LESSONS: Down syndrome patients with cerebral abscess have a high morbidity rate, mainly due to cardiac disease. Therefore, early diagnostic workup, including echocardiography, allows proactive management with an improved outcome. https://thejns.org/doi/10.3171/CASE23394.

Treatment strategy and therapy based on immune response in patients with gastric cancers.

In this editorial, we highlight the significance of a retrospective study "Analysis of the impact of immunotherapy efficacy and safety in patients with gastric cancer and liver metastasis" performed by Liu et al. The authors utilized data collected from gastric cancer (GC) patients and assessed immunotherapy effectiveness and survival status. They found significant differences in treatment response. Because immunotherapy seems to be a beneficial strategy for advanced GC patients, stratification of the data based on metastasis status may further improve treatment strategies.

Evaluation of Treatment Strategies and Survival of Patients with cT4bM0 Esophageal Cancer: A Nationwide Cohort Study.

INTRODUCTION: The optimal therapeutic strategy for patients with cT4bM0 esophageal cancer is controversial and varies internationally. This study aimed to describe treatment and survival of patients with cT4bM0 esophageal cancer in the Netherlands. METHODS: Patients staged with cT4bM0 esophageal cancer who were registered in the Netherlands Cancer Registry (NCR) were included. All patients were categorized by the treatment modality received. The Kaplan-Meier method was used to estimate the overall survival of them. RESULTS: Between 2015 and 2020, 286 patients with cT4bM0 esophageal cancer were included. Treatment consisted of preoperative chemoradiotherapy/chemotherapy followed by surgery (8%), chemoradiotherapy alone (35%), chemotherapy alone (6%), radiotherapy alone (19%), and best supportive care (32%). The median follow-up was 28.1 months. The 1-, 3-, and 5-year survival rates of each group were 82%, 58%, 49% for preoperative therapy plus surgery; 53%, 27%, 16% for chemoradiotherapy only; 13%, 0%, 0% for chemotherapy only; 13%, 0%, 0% for radiotherapy only; and 5%, 0%, 0% for best supportive care. CONCLUSION: In a selected group of patients, preoperative therapy followed by esophagectomy may lead to improved survival, which is comparable to patients with <cT4bM0 tumors. Therefore, reevaluation following chemo(radio)therapy is recommended in these patients to evaluate the possibility of additional surgical resection.

Enhancing targeted tumor treatment: A novel fuzzy logic framework for precision drug delivery strategy selection.

OBJECTIVE: This study aims to address the challenge of selecting optimal drug delivery strategies for tumor patients by introducing a novel theoretical framework. METHODS: We propose a fuzzy logic-based framework for quantitatively assessing Health States (HS) in tumor patients. This framework integrates quantified HS assessments with causality strength analyses, offering a comprehensive understanding of various drug delivery schemes' effectiveness from pharmacokinetic and pharmacodynamic perspectives. RESULTS: The efficacy of our approach is demonstrated through a series of real-world patient case studies, highlighting its potential to enhance the evaluation and selection of targeted drug delivery strategies. CONCLUSION: Our work contributes to the field by showcasing practical applications of fuzzy logic in targeted drug delivery systems (TDDs) and establishing a new benchmark for precision in drug delivery strategy selection. SIGNIFICANCE: This study has significant implications for developing personalized medical treatments, potentially revolutionizing the field with a more nuanced and scientifically rigorous method for evaluating and selecting drug delivery protocols. CONTRIBUTIONS: Development of a fuzzy logic framework for precise quantification of health states in tumor patients. Innovative integration of a causal system for comprehensively evaluating targeted drug delivery strategies.

Hepatocellular adenomas with severe intra-abdominal bleeding, related to an underlying coagulation disorder: a case report.

BACKGROUND: Hepatocellular adenoma is a rare benign liver tumor. Typically, hepatocellular adenomas are solitary and are found in young women who use estrogen-containing contraceptives. The occurrence of multiple hepatocellular adenoma has been linked to higher body mass index, and as the prevalence of overweight increases, multiple hepatocellular adenomas are seen more often. An hepatocellular adenoma does not always necessitate treatment, as they can regress under conservative strategies. In incidental cases, an adenoma presents owing to bleeding, which is mostly self-limiting. If it is not, embolization of hepatic involved vessels is indicated. CASE PRESENTATION: In this case report, we discuss a 42-year old Caucasian woman with multiple hepatocellular bleeds, treated by multiple endovascular procedures. After the first embolization of an adenoma in the right liver lobe, a second bleed occurred in the left lobe, necessitating additional endovascular intervention. During admittance, treatment was complicated by pulmonary embolism and a pneumonia. During follow-up, our patient was diagnosed with antiphospholipid syndrome. CONCLUSION: Hepatocellular adenoma is a rare diagnosis that requires centralized expertise. This particular case illustrates the complexity of treatment strategies for associated intra-abdominal bleeding and possible complications. Although liver adenoma is often an incidental finding, it can also result in significant morbidity. Centralization of treatment leads to expertise in managing complex treatment strategies.

Retrospective, observational study of different medication regimens and outcome in children with cough variant asthma.

OBJECTIVE: This retrospective longitudinal cohort study aimed to explore the best therapeutic regimen and treatment duration of cough variant asthma (CVA) in children. METHODS: A total of 314 children with CVA were divided into receive inhaled corticosteroids (ICS) combined with long-acting beta2-agonist (LABA) group, ICS combined with leukotriene receptor antagonists (LTRA) group, ICS monotherapy group and LTRA monotherapy group. All clinical data were statistically analyzed. Logistic regression model was used to compare the advantages and disadvantages of different treatment schemes at each follow-up time point and the best treatment scheme. The Cox proportional hazard regression model based on inverse probability weighting was used to compare the effects of different medication regimens on adverse outcomes with asthma recurrence or progression as the end point. RESULTS: (1) After comprehensive analysis, ICS + LABA group was the preferred control regimen for CVA within 8 weeks. After 8 weeks of diagnosis, the efficacy of ICS group or LTRA group was comparable to that of ICS + LABA group and ICS + LTRA group. (2) The ICS + LABA group showed a significant improvement in cough at an early stage, particularly at 4 weeks; the symptoms of ICS + LTRA and ICS groups were significantly improved at 36 weeks. The LTRA group alone showed significant improvement at 20 weeks. CONCLUSION: ICS + LABA, ICS + LTRA, ICS alone and LTRA alone can effectively treat CVA. ICS + LABA could improve the symptoms most quickly within 8 weeks after CVA diagnosis, followed by ICS + LATR group. After 8 weeks, it can be reduced to ICS alone to control CVA for at least 36 weeks based on the remission of symptoms in children.

Prognostic factors and treatment strategies of limited-stage primary esophageal small-cell carcinoma-a SEER database analysis.

Background: Primary esophageal small-cell carcinoma (PESC) is a rare tumor with poor efficacy, and there is currently no standardized treatment method. Our aim is to explore the prognostic factors and possible optimal treatment modalities for limited-stage PESC. Methods: We retrospectively searched the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2019 for data of patients with limited-stage PESC. Kaplan-Meier method was used to plot survival curves, calculate survival rates, and Log-rank was used to test the differences among survival curves. Prognostic factors were explored through univariate and multivariate Cox regression survival analyses; Cox regression survival analysis was also conducted to analyze the risk of death among treatment groups and compare the survival differences among each treatment group. The non-single treatment (ST) group was defined as the comprehensive treatment (CT) group and it was compared against the ST group. Results: A total of 186 cases of limited-stage PESC were included in the study, there were differences in survival time among different groups due to differences in age, year, median household income, and N stage (P<0.001, P=0.041, P=0.002, P=0.001). The median overall survival (mOS) of the surgical group (19 months) was longer than that of the nonsurgical group (11 months) (P=0.01). The mOS of the chemotherapy group (16 months) was longer than that of the non-chemotherapy group (4 months) (P<0.001). The mOS of the radiotherapy group (16 months) was longer than that of the non-radiotherapy group (8 months) (P<0.001). Univariate analysis showed that age ≥80 years (P=0.006), year (1997-2007) (P=0.01), year (2008-2019) (P=0.01), N2 (P=0.003), surgery (P=0.02), radiotherapy (P<0.001), and chemotherapy (P<0.001) were prognostic factors affecting overall survival (OS) in limited-stage PESC patients. Multivariate analysis showed that SEER stage (P=0.02), age (P=0.007), radiotherapy (P<0.001), surgery (P=0.006), and chemotherapy (P<0.001) were independent prognostic factors affecting OS in patients of limited-stage PESC. Prognosis was better in the non-monotherapy group than in each monotherapy group. The CT group is superior to the ST group (P<0.001). The surgery combined with chemotherapy (SC) group had the longest mOS and the highest reduced risk of death, but there was no statistical difference. Conclusions: SEER stage, age, radiotherapy, chemotherapy, and surgery were independent prognostic factors in limited-stage patients; CT outperformed ST; the SC group had the longest median survival, but showed no statistical difference.

Early psoriatic arthritis: when is the right time to start advanced therapy?

Despite significant advances in the treatment of psoriatic arthritis (PsA) in the last two decades, remission remains elusive and there is no cure. Evidence from rheumatoid arthritis (RA) confirming enhanced response and outcome from earlier treatment intervention suggests the plausibility of the window of opportunity in the pathogenesis of RA. Yet, data are lacking in PsA. Although treatment response may be enhanced in shorter disease duration, it is unknown how this early intervention may impact long-term outcomes. Furthermore, it remains to be demonstrated whether there is a best treatment strategy and time of intervention. Crucially, the main hurdle when aiming for early treatment intervention is the ability to achieve a timely diagnosis that highlights the need to focus research efforts on characterizing the very early disease stages including the transition to PsA in the at-risk psoriasis population.

Advances in Molecular Pathology, Diagnosis and Treatment of Spinal Cord Astrocytomas.

Spinal cord astrocytoma (SCA) is a rare subtype of astrocytoma, posing challenges in diagnosis and treatment. Low-grade SCA can achieve long-term survival solely through surgery, while high-grade has a disappointing prognosis even with comprehensive treatment. Diagnostic criteria and standard treatment of intracranial astrocytoma have shown obvious limitations in SCA. Research on the molecular mechanism in SCA is lagging far behind that on intracranial astrocytoma. In recent years, huge breakthroughs have been made in molecular pathology of astrocytoma, and novel techniques have emerged, including DNA methylation analysis and radiomics. These advances are now making it possible to provide a precise diagnosis and develop corresponding treatment strategies in SCA. Our aim is to review the current status of diagnosis and treatment of SCA, and summarize the latest research advancement, including tumor subtype, molecular characteristics, diagnostic technology, and potential therapy strategies, thus deepening our understanding of this uncommon tumor type and providing guidance for accurate diagnosis and treatment.

Gastric cancer in pregnancy: a review.

Malignant tumors including gastric cancer (GC) are the leading cause of deaths among reproductive women. Physiological morning sickness can mask the clinical manifestations of GC, whereas the clinical presence of metastatic tumors in the abdominal cavity may be easily mistaken for abdominal swelling caused by fetal growth. Pregnancy and delivery processes in young females could accelerate the growth of GC, leading to its rapid development and grave prognosis. Therefore, early diagnosis is critical and gastrointestinal endoscopy is recommended for any suspected pregnant woman with long-term morning sickness. Treatment strategies, including chemotherapy, resection surgery and radiotherapy, will be determined based on a comprehensive consideration of the status of both the fetus and the mother. Rational management, especially clinical multidisciplinary collaboration may significantly benefit such patients.

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CDK4/6 and aromatase inhibitors as first-line treatment in metastatic high-grade neuroendocrine carcinoma of the breast: A case report.

Key Clinical Message: There is no consensus regarding the therapeutic approach of breast neuroendocrine carcinomas (NECs). As most NECs are hormone receptor positive and HER-2 negative, we suggest that endocrine-based strategies may play a leading role. Here, we report a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium. Abstract: Primary neuroendocrine neoplasms of the breast constitute a rare entity. They are characterized by predominant neuroendocrine differentiation and are further divided into well-differentiated neuroendocrine tumors and poorly differentiated (high-grade) neuroendocrine carcinomas (NECs). Regarding their therapeutic approach, there are no standardized guidelines. Herein, we present the first case ever reported, concerning a female patient with de novo metastatic breast NEC who received hormonal therapy, a combination of a CDK4/6 inhibitor palbociclib with letrozole and triptorelin, as first-line treatment with significant clinical and radiological response. As most NECs are estrogen receptor and/or progesterone receptor positive and HER-2 negative, we suggest that hormonal therapy may play a leading role even in the first-line setting. The present report provides a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium of breast NECs.

MEK-inhibitor treatment reduces the induction of regulatory T cells in mice after influenza A virus infection.

Regulatory T cells (Tregs) play a crucial and complex role in balancing the immune response to viral infection. Primarily, they serve to regulate the immune response by limiting the expression of proinflammatory cytokines, reducing inflammation in infected tissue, and limiting virus-specific T cell responses. But excessive activity of Tregs can also be detrimental and hinder the ability to effectively clear viral infection, leading to prolonged disease and potential worsening of disease severity. Not much is known about the impact of Tregs during severe influenza. In the present study, we show that CD4+/CD25+FoxP3+ Tregs are strongly involved in disease progression during influenza A virus (IAV) infection in mice. By comparing sublethal with lethal dose infection in vivo, we found that not the viral load but an increased number of CD4+/CD25+FoxP3+ Tregs may impair the immune response by suppressing virus specific CD8+ T cells and favors disease progression. Moreover, the transfer of induced Tregs into mice with mild disease symptoms had a negative and prolonged effect on disease outcome, emphasizing their importance for pathogenesis. Furthermore, treatment with MEK-inhibitors resulted in a significant reduction of induced Tregs in vitro and in vivo and positively influenced the progression of the disease. Our results demonstrate that CD4+/CD25+FoxP3+ Tregs are involved in the pathogenesis of severe influenza and indicate the potential of the MEK-inhibitor zapnometinib to modulate CD4+/CD25+FoxP3+ Tregs. Thus, making MEK-inhibitors even more promising for the treatment of severe influenza virus infections.