Rapid Progression Research Articles

High mitochondrial DNA content is a key determinant of stemness, proliferation, cell migration, and cancer metastasis in vivo

Here, we examined the potential role of mitochondrial DNA (mtDNA) levels in conveying aggressive phenotypes in cancer cells, using two widely-used breast cell lines as model systems (MCF7[ER+] and MDA-MB-231[ER-]). These human breast cancer cell lines were fractionated into mtDNA-high and mtDNA-low cell sub-populations by flow cytometry, using SYBR Gold as a vital probe to stain mitochondrial nucleoids in living cells. Enrichment of mtDNA-high and mtDNA-low cell sub-populations was independently validated, using a specific DNA-binding mAb probe (AC-30-10), and mitochondrial-based functional assays. As predicted, mtDNA-high MCF7 cells showed significant increases in mitochondrial mass, membrane potential, and superoxide production, as well as increased mitochondrial respiration and ATP production. Moreover, mtDNA-high MCF7 cells demonstrated increases in stemness features, such as anchorage-independent growth and CD44 levels, as well as drug-resistance to Gemcitabine and Tamoxifen. Proliferation rates were also significantly increased, with a dramatic shift towards the S- and G2/M-phases of the cell cycle; this was indeed confirmed by RNA-Seq analysis. Complementary results were obtained with MDA-MB-231 cells. More specifically, mtDNA-high MDA-MB-231 cells showed increases in stemness features and ATP production, as well as rapid cell cycle progression. Moreover, mtDNA-high MDA-MB-231 cells also exhibited increases in both cell migration and invasion, suggesting a role for mtDNA in distant metastasis. To test this hypothesis more directly, a preclinical in vivo model was utilized. For this purpose, MDA-MB-231 tumour cell grafts were treated with an established mtDNA synthesis inhibitor, namely Alovudine (3’-deoxy-3’-fluorothymidine). As expected, drug-induced depletion of mtDNA led to a shift from mitochondrial to glycolytic metabolism. Interestingly, Alovudine very effectively reduced the formation of spontaneous metastases by nearly 70%, but minimally inhibited tumour growth by approximately 20%. Taken together, these data suggest that high mtDNA content is a key driver of stemness, proliferation, and migration, as well as cancer cell metastasis.

Salient object detection with bayesian inference based on radar and camera fusion used in UAV obstacle avoidance

Most existing salient object detection methods are sensitive to background noise and rely on prior information in UAV obstacle avoidance applications despite detection methods witnessing rapid progress. In this paper, we propose an efficient framework for salient object detection based on radar-camera fusion and iterative Bayesian optimization. A rough salient object (RSO) image is first built through radar and camera calibration. Next, the RSO image is used to calculate the edge response based on the receptive field mechanism of the primary visual cortex to construct the contour image. Finally, the above two images and the 2D Gaussian distribution are jointly integrated into an iterative Bayesian optimization scheme to get the final salient object image. Different from typical detection methods, this method suppresses background noise by filtering out irrelevant pixels using fusion information. The Bayesian inference framework’s detection performance is improved by precise spatial prior, consisting of optimized contour and RSO images. Experimental results indicate that the presented algorithm performs well against state-of-the-art salient object detection methods on several reference datasets in different evaluation metrics.

Age-Related Changes in Heart Rate Variability from the Neonatal Period to Adulthood.

The aim of the study was to reveal the patterns of the age-related dynamics of the frequency-dependent regulation of heart rate variability (HRV) based on the analysis of Holter ECG recordings from healthy subjects of four age groups: neonates, one-year-old infants, adolescents, and adults. A wide spectral composition of HRV is shown, consisting of nine Hilbert-Huang modes in the frequency range from 0.0001 to 2 Hz. A decrease in the central frequencies of all modes is shown in the postnatal period with a plateau in adolescence. A rapid progression of systemic humoral regulation of HRV, characterized by a consolidated increase in the amplitudes of the corresponding modes with a plateau in adolescence, is demonstrated. The dome-shaped character of age-related changes in amplitude of modes associated with autonomic control with a maximum in adolescence is shown. The results obtained quantitatively demonstrate age-related consolidated changes in HRV parameters from neonates to adulthood.

Pulmonary-Renal Syndrome in the Elderly: Immunosuppressive Treatment – Case Report

Pulmonary-renal syndrome is called alveolar hemorrhage accompanied by glomerulonephritis. The above condition can occur as a manifestation of ANCA-associated granulomatosis with vasculitis. The course of the disease varies from mild, limited inflammation to rapid progression with multi-organ changes that can be life-threatening. The mainstay of therapy is immunosuppression - both in the acute phase of the disease and after clinical improvement. Unfortunately, common causes of death in addition to complications of the disease include side effects of immunosuppressive treatment. A 72-year-old man is transferred to the Nephrology Unit for acute kidney injury of unclear etiology. On the basis of clinical examination, laboratory and imaging studies, a diagnosis of systemic small vessel inflammation with c-ANCA occupying the kidneys, lungs and intestines was made. Due to acute respiratory failure, the patient was transferred to the ICU, where renal replacement therapy, plasmapheresis, steroid pulses and cyclophosphamide were administered. After clinical improvement, it was decided to continue cyclophosphamide therapy and monitor blood IgG levels. Unfortunately, 4 months later, the patient died of multiple organ failure caused by septic shock of bacterial etiology. In the described case, age and comorbidities were the biggest risk factors for infectious complications of immunosuppression. The population is aging, so it is necessary to analyze the current standards of immunosuppressive treatment to improve the prognosis of the elderly.

Unraveling the interplay of β-amyloid pathology and Parkinson's disease progression: Insights from autopsy-confirmed patients

BackgroundParkinson's disease (PD) is a prevalent neurodegenerative disorder that manifests with both motor and non-motor symptoms, with α-synuclein misfolding recognized as a key contributor. Cognitive decline in advanced PD stages prompts interest in amyloid deposition, a hallmark of Alzheimer's disease (AD), as a potential factor. This study explores the impact of β-amyloid (Aβ) pathology in PD patients on disease progression, aiming to elucidate the role of Aβ in PD development and progression. MethodsThis study included autopsy-confirmed PD patients with post-mortem analyses from the Parkinson's Progression Markers Initiative. Comprehensive clinical assessments, including demographic data, clinical features, CSF markers, and neuroimaging, were conducted. Statistical analyses assessed differences between groups based on the severity of AD neuropathological changes. ResultsAll 16 PD participants exhibited severe Lewy body pathology, with 75 % displaying AD neuropathological changes. At baseline, PD patients with severe or moderate AD neuropathological changes had a lower Aβ42 levels (p = 0.022) and Aβ42/tau ratio (p = 0.001). Longitudinal follow-up data indicated that individuals with severe or moderate AD neuropathological changes exhibited a more rapid decline in MOCA score and BJLOT score, along with a quicker increase in MDS-UPDRS Ⅲ score. ConclusionsThe study underscores the presence of severe Aβ pathology in PD, suggesting a role in accelerated disease progression. Cross-seeding between Aβ and α-synuclein may contribute to rapid clinical symptom progression. Further research is needed for a comprehensive understanding of neurodegenerative disease complexities and exploring potential therapeutic interventions targeting protein aggregation.

Redesain User Interface Pada Website Arlang Tour and Travel Menggunakan Metode User Centered Design Sebagai Media Promosi

The development of information technology in Indonesia, particularly in the tourism sector, has experienced rapid progress. Tourism in Indonesia has become one of the main pillars in supporting national economic growth. CV. Arlang Tour and Travel, a travel agency, has also contributed to this sector. However, their website is still not optimal in terms of attractiveness and completeness of information. The initial survey results, conducted using the System Usability Scale, showed an average score of 52 from 30 respondents, with a grade scale of D, indicating that the website's usability is still below average. This research aims to evaluate and redesign the website, focusing on enhancing content completeness using the User Centered Design (UCD) method for design development, while the System Usability Scale (SUS) questionnaire is applied for evaluation. After the redesign using the UCD method, there was an improvement, with the average score reaching 80 with a grade scale of B. These changes successfully addressed the main issues related to content completeness and improved promotions to expand reach, which is expected to provide a better user experience. This is anticipated to contribute to an overall improvement in user experience and strengthen the image of Arlang Tour and Travel in the tourism industry.

Rapid Evolution of Metastases in Patients with Treated G3 Neuroendocrine Tumors Associated with NEC-Like Transformation and TP53 Mutation.

Little is known about the morphomolecular features of G3 neuroendocrine tumors (G3NETs) under prolonged systemic treatments, although rapid progression is increasingly observed. This longitudinal study aims to elucidate the course and morphomolecular features of metastasized G3NETs with high-grade transformation. Clinical and histological findings in 40 patients with metastasized and treated G3NETs, which were histologically examined at least twice with an interval time of more than 6 months (median 27), were reviewed and the morphomolecular changes recorded and assigned to treatment. Neuroendocrine carcinoma (NEC)-like histology defined by high-grade atypia, diffuse growth pattern, and/or necrosis was identified in nine (22%) G3NETs (seven pancreatic, two rectal) patients. All NEC-like tumors showed a significantly higher Ki67 increase and longer interval time betweenfirst and last examination than non-NEC-like G3NETs (53 vs. 19% and 60 vs. 24 months, respectively). Moreover, all NEC-like G3NETs had TP53 (100%), but rarely RB1 (12%) mutations, and retained NET-typical mutations such as MEN1 or DAXX (five of the pancreatic NETs). The last treatments received prior to the NEC-like transformation included PRRT (n = 3), somatostatin analog, everolimus, sunitinib (n = 1 each), and alkylating agents (n = 2). Abrupt clinical progression in patients with metastasized G3NETs is associated with a significant increase in Ki67, accelerated growth, and NEC-like histology. These findings are most likely attributable to the novel TP53 mutation, which was detected in all nine cases at the last evaluation. However, none of the cases exhibited a complete transformation to a typical NEC, as the tumors retained partial histological and genetic features of NETs.

Serum metabolomics analysis reveals potential biomarkers of penicillins-induced fatal anaphylactic shock in rats

Immunoglobulin E (IgE)-mediated immediate hypersensitivity reactions are the most concerning adverse events after penicillin antibiotics (PENs) administration because of their rapid progression and potential for fatal outcome. However, the diagnosis of allergic death is a forensic challenge because it mainly depends on nonspecific characteristic morphological changes, as well as exclusion and circumstantial evidence. In this study, an untargeted metabolomics approach based on liquid chromatography-mass spectrometry (LC-MS) was used to screen potential forensic biomarkers of fatal anaphylactic shock induced by four PENs (benzylpenicillin (BP), amoxicillin (AMX), oxacillin (OXA), and mezlocillin (MEZ)), and analyzed the metabolites, metabolic pathway and the mechanism which were closely related to the allergic reactions. The metabolomics results discovered that a total of 24 different metabolites in all four anaphylactic death (AD) groups, seven of which were common metabolites. A biomarker model consisting of six common metabolites (linoleic acid, prostaglandin D2, lysophosphatidylcholine (18:0), N-acetylhistamine, citric acid and indolelactic acid) AUC value of Receiver Operating Characteristic (ROC) curve was 0.978. Metabolism pathway analysis revealed that the pathogenesis of PENs-induced AD is closely related to linoleic acid metabolism. Our results revealed that the metabolomic profiling has potential in PENs-induced AD post-mortem diagnosis and metabolic mechanism investigations.

CircMETTL3-156aa reshapes the glycolytic metabolism of macrophages to promote M1 polarization and induce cytokine storms in sHLH

Persistent macrophage activation and cytokine storms are critical causes for the rapid disease progression and high mortality rate of Secondary Hemophagocytic lymphohistiocytosis (sHLH). Identification of key regulatory factors that govern the activation of macrophages is vital. Plasma exosomal circular RNAs (circRNAs) are considered important biomarkers and potential therapeutic targets for various diseases, however, their function in sHLH is still unclear. In this study, we demonstrated for the first time that circMETTL3, derived from METTL3, is upregulated in sHLH patient plasma exosomes, which may plays an important role in the diagnosis of sHLH. Significantly, we also revealed that a novel peptide encoded by circMETTL3, METTL3-156aa, is an inducer of M1 macrophage polarization, which is responsible for the development of cytokine storms during sHLH. We then identified that METTL3-156aa binding with lactate dehydrogenase A (LDHA) and promotes M1 macrophage polarization by enhancing macrophage glycolysis. Additionally, the glycolysis metabolite lactate upregulates the cleavage factor SRSF10 expression by lactylation. This results in increased splicing of the pre-METTL3 mRNA, leading to an enchance in the production of cirMETTL3. Therefore, our results suggest that the circMETTL3/METTL3-156aa/LDHA/Lactate/SRSF10 axis forms a positive feedback loop and may be a novel therapeutic target for the treatment of sHLH.

Revising LH cut-off for the diagnosis of central precocious puberty via triptorelin stimulation assay.

Precocious puberty (PP) in girls is defined by thelarche before age 8. The diagnostic gold standard is an increased LH level following gonadotropin-releasing hormone (GnRH) stimulation. Alternatively, GnRH analogues like triptorelin can be used, though their interpretation varies. Since 2000, we have used a triptorelin-induced LH cut-off of 15 IU/L, 4 h post-stimulus. However, many girls showed LH values below this threshold despite evident pubertal progression. To establish a new LH threshold post-triptorelin stimulation for earlier diagnosis of central precocious puberty (CPP) in girls showing pubertal progression and to evaluate additional parameters for diagnostic accuracy. We enrolled 186 girls with thelarche onset between ages 1-8 and a GnRH analogue assay performed between 2015-2019 without signs of axis activation. Within this cohort, 62 patients repeated the triptorelin test due to rapid pubertal progression. The assay involved administering 100 mcg/m² of triptorelin and measuring LH, FSH, and estradiol levels before and four hours post-injection. Patients with axis activation at the second test had significantly higher post-stimulus LH levels at the first test compared to those below 15 IU/L. They also had higher basal LH levels, elevated LH/FSH ratio, and increased growth velocity. Statistical analysis identified a new post-stimulus LH threshold of 5 IU/L. We propose a LH value of 5 IU/L after triptorelin administration as a new threshold for early CPP diagnosis. While the LH/FSH ratio and growth velocity are associated with axis activation, they did not significantly enhance diagnostic accuracy when combined with the LH value.

Rocky Mountain Spotted Fever Encephalitis and "Starry Sky" Pattern on MRI: A Case Report.

Rocky Mountain Spotted Fever (RMSF) is a tick-borne disease caused by Rickettsia rickettsii (R. rickettsii). RMSF presents after a tick bite with fever, rash, and headache but can also cause more serious neurological manifestations. We report a case of RMSF encephalitis presenting with altered sensorium and rapid progression to coma, fever, and petechial rash, and an magnetic resonance imaging (MRI) brain notable for a "starry sky" pattern. A 61-year-old woman presented with confusion and fever and was diagnosed with a urinary tract infection. Two days later, she became comatose. MRI brain revealed lacunar infarcts in the right centrum semiovale and splenium of the corpus callosum. Lumbar puncture was notable for neutrophilic pleocytosis and elevated protein with negative bacterial and viral cultures. Empiric meningitis therapy was initiated, and she was transferred to our institution. On transfer, she was febrile, comatose, and had a diffuse petechial rash. Repeat MRI brain demonstrated diffuse, innumerable punctate foci of diffusion restriction with susceptibility-weighted signal attenuation throughout cerebral hemispheres in a "starry sky" pattern. Skin biopsy revealed perivascular lymphocytic infiltrates. Serologic RSMF antibody titers were obtained, and doxycycline was initiated for presumed RMSF encephalitis. The family opted to pursue palliative measures, given no clinical improvement. RSMF titers and postmortem PCR from brain tissue were positive for R. rickettsii. This case report highlights the clinical presentation of RMSF encephalitis. RMSF encephalitis should be suspected in a patient presenting with encephalopathy, fever, petechial rash, and MRI brain findings of diffuse punctate foci of diffusion restriction and susceptibility-weighted signal attenuation in a "starry-sky" pattern.

Nanopore-based full-length transcriptome sequencing for understanding the underlying molecular mechanisms of rapid and slow progression of diabetes nephropathy.

Diabetic nephropathy (DN) has been a major factor in the outbreak of end-stage renal disease for decades. As the underlying mechanisms of DN development remains unclear, there is no ideal methods for the diagnosis and therapy. We aimed to explore the key genes and pathways that affect the rate progression of DN. Nanopore-based full-length transcriptome sequencing was performed with serum samples from DN patients with slow progression (DNSP, n = 5) and rapid progression (DNRP, n = 6). Here, transcriptome proclaimed 22,682 novel transcripts and obtained 45,808 simple sequence repeats, 1,815 transcription factors, 5,993 complete open reading frames, and 1,050 novel lncRNA from the novel transcripts. Moreover, a total of 341 differentially expressed transcripts (DETs) and 456 differentially expressed genes (DEGs) between the DNSP and DNRP groups were identified. Functional analyses showed that DETs mainly involved in ferroptosis-related pathways such as oxidative phosphorylation, iron ion binding, and mitophagy. Moreover, Functional analyses revealed that DEGs mainly involved in oxidative phosphorylation, lipid metabolism, ferroptosis, autophagy/mitophagy, apoptosis/necroptosis pathway. Collectively, our study provided a full-length transcriptome data source for the future DN research, and facilitate a deeper understanding of the molecular mechanisms underlying the differences in fast and slow progression of DN.

Angioinvasive Rhino-Orbital-Cerebral Mucormycosis in a Patient with Type 2 Diabetes Mellitus: A Complex and Lethal Cause of Stroke

Rhino-orbital-cerebral mucormycosis is a rapidly progressive and often fatal fungal infection caused by molds of the order Mucorales, particularly affecting immunocompromised individuals. This infection is notorious for its angioinvasive properties, enabling the fungi to invade blood vessels and leading to tissue necrosis. We report the clinical course of a 59-year-old Caucasian man with poorly controlled type 2 diabetes (HbA1c 16.8%) who presented with unilateral headache, left-sided facial numbness, and incomplete left ocular motor paresis. Initial presentation raised suspicion of orbital phlegmon, leading to antibiotic and later corticosteroid pulse therapy, which worsened the patient’s condition. Subsequent imaging demonstrated extensive inflammatory changes, including wall irregularities of the left intracranial internal carotid artery, accompanied by ocular protrusion and periorbital enhancement. New palatal lesions indicated mucormycosis, which was confirmed by molecular analysis of a palatal biopsy, leading to Amphotericin B treatment. Pre-surgery imaging revealed a malignant middle cerebral artery infarction, and the patient died 16 days after symptom onset and 12 days after initial presentation under palliative care due to a poor prognosis. This case of angioinvasive mucormycosis underscores the severe and often fatal course of rhino-orbital-cerebral mucormycosis in an immunocompromised individual. The rapid progression from initially vague and unspecific symptoms to extensive vascular involvement and stroke highlights the critical need for early and accurate diagnosis, as well as prompt intervention to prevent further disease progression. Additionally, this case also illustrates the potential risks associated with corticosteroid therapy in the presence of undiagnosed fungal infections, which can exacerbate the condition and lead to serious complications. Clinicians should maintain a high index of suspicion for mucormycosis in similar clinical scenarios, prioritizing adequate antifungal treatment and careful monitoring to improve patient outcomes. Early interdisciplinary collaboration is essential for the effective management of such complex cases.

Concurrent Image Differentiation and Integration Processings Enabled By Polarization‐Multiplexed Metasurface

AbstractOptical computing and image processing performed by sensor front‐end metasurfaces is receiving increasing interest because of advantages such as significant reduction of latency time, energy consumption, and system complexity. Despite the rapid progress, concurrent processing, the most important feature of electronic computing, has not yet been well implemented in optical computing. Here, a metasurface‐based optical image processor that can perform optical differentiation and integration tasks simultaneously is proposed. This optical front‐end processor integrates two coherent transfer functions corresponding to differential and integral convolution kernels into a built‐in metasurface by polarization encoding, allowing concurrent processing of multiple all‐optical computational tasks. The simultaneous differentiation and integration operations on images for edge enhancement and denoising are demonstrated at multiple visible wavelengths. This concurrent processing architecture paves a promising pathway toward multifunctional and higher‐speed image processing for machine vision and biomedical imaging and shows the potential to expedite and potentially supplant certain digital neural network algorithms.

Machine learning-based diagnostic prediction of minimal change disease: model development study

Minimal change disease (MCD) is a common cause of nephrotic syndrome. Due to its rapid progression, early detection is essential; however, definitive diagnosis requires invasive kidney biopsy. This study aims to develop non-invasive predictive models for diagnosing MCD by machine learning. We retrospectively collected data on demographic characteristics, blood tests, and urine tests from patients with nephrotic syndrome who underwent kidney biopsy. We applied four machine learning algorithms—TabPFN, LightGBM, Random Forest, and Artificial Neural Network—and logistic regression. We compared their performance using stratified 5-repeated 5-fold cross-validation for the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC). Variable importance was evaluated using the SHapley Additive exPlanations (SHAP) method. A total of 248 patients were included, with 82 cases (33%) were diagnosed with MCD. TabPFN demonstrated the best performance with an AUROC of 0.915 (95% CI 0.896–0.932) and an AUPRC of 0.840 (95% CI 0.807–0.872). The SHAP methods identified C3, total cholesterol, and urine red blood cells as key predictors for TabPFN, consistent with previous reports. Machine learning models could be valuable non-invasive diagnostic tools for MCD.

Allogeneic CAR-T cells for cancer immunotherapy.

Autologous chimeric antigen receptor (CAR)-modified T (CAR-T) cell therapy has displayed high efficacy in the treatment of hematological malignancies. Up to now, 11 autologous CAR-T cell products have been approved for the management of malignancies globally. However, the application of autologous CAR-T cell therapy has many individual limitations, long time-consuming, highly cost, and the risk of manufacturing failure. Indeed, some patients would not benefit from autologous CAR-T cell products because of rapid disease progression. Allogeneic CAR-T cells especially universal CAR-T (U-CAR-T) cell therapy are superior to these challenges of autologous CAR-T cells. In this review, we describe basic study and clinical trials of U-CAR-T cell therapeutic methods for malignancies. In addition, we summarize the problems encountered and potential solutions.

Spinal Diffuse Midline Glioma H3 K27M-Altered: Report of a Rare Tumor with Extracranial Skeletal Metastases and Review of Literature.

Diffuse midline glioma, H3 K27-altered is a rare and aggressive pediatric brain tumor with a grim prognosis. Diffuse midline glioma is characterized by specific molecular alterations, including H3 K27 mutations, and involves deep midline structures such as the brainstem, cerebellum, spinal cord, and thalamus. These tumors present with a classic triad of symptoms and have limited surgical options due to their challenging locations. Extra-neural metastases are an unusual occurrence in diffuse midline glioma and have been rarely described. Here we report a 17-year-old girl with spinal diffuse midline glioma, H3 K27M-mutant, who presented with multiple metastatic osseous lesions confirmed on biopsy of the thoracic vertebral lesion. Due to the rapid disease progression, the patient was recommended palliative therapy. Extra-neural metastases in diffuse midline glioma are rare, with only 16 reported patients, and no standard therapy exists. An accurate and early diagnosis is necessary to develop a personalized plan of treatment. Further research is needed to gain insights into the molecular pathology of diffuse midline glioma, H3 K27-altered, and improve the quality of life and the outcome of patients with this deadly disease.

Clinical correlates and pathology of non-diabetic renal disease in diabetes mellitus

Objectives: Early identification and differentiation of patients with non-diabetic renal disease (NDRD) from diabetic nephropathy (DN) or those with NDRD superimposed on DN improves the prognosis and reduces associated morbidity. The objectives of the study were to compare the clinical profile, nature of renal involvement, and etiopathogenesis (renal biopsy) of patients with isolated NDRD and NDRD superimposed on DN. Materials and Methods: It is a descriptive study in patients with T2D and renal involvement suggestive of non-diabetic etiology further evaluated with renal biopsy and grouped as NDRD alone or NDRD with DN. Results: Of the total 50, 66% were male, the mean age was 55.57 ± 12.28 years, and all were proteinuric. Overall, isolated NDRD and NDRD superimposed on DN were observed in 64% and 36% of patients, respectively. Diabetic retinopathy was absent in 82% of cases. The most common finding in isolated NDRD was membranous nephropathy, followed by immunoglobulin A (IgA) nephropathy and rapid progression of glomerular nephritis (RPGN). At the same time, in the NDRD and DN group, maximum patients displayed IgA nephropathy followed by acute tubular necrosis and RPGN. The incidence of atypical features of renal disease was almost twice as high in the isolated NDRD group than in the group with both NDRD + DN. Conclusion: NDRDs are highly prevalent, and DN may superimpose these. Recognizing NDRD solely on the basis of clinical indicators is challenging. Therefore, histopathological analysis seems essential to accurately diagnose NDRD in diabetic patients to reduce the probability of missed NDRD diagnosis and initiate prompt treatment.

Redefining chimeric antigen receptor T-cell (CAR-T) regulation: China's responses to address secondary cancer risks of CAR-T therapy.

Since the United States Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell (CAR-T) therapy in 2017, it has marked a major breakthrough in cancer treatment, leading to a surge in global research and applications in this field. In recent years, China has made rapid progress, quickly catching up through heavy investment in CAR-T construction, preparation processes, and treatment strategies. China's CAR-T therapy market is driven by substantial pharmaceutical investment targeting its vast population, yet high therapy costs remain uncovered by basic medical insurance. In November 2023, FDA issued a warning about the risk of secondary cancers in patients undergoing CAR-T therapy, sparking global concern. In fact, the China National Medical Products Administration (NMPA) preemptively implemented a series of measures to address the safety concerns of CAR-T therapy, emphasizing the risk of secondary cancers and advising lifelong monitoring as part of the approval process for CAR-T products. Nevertheless, additional regulatory measures are needed to address emerging risks, particularly the threat of secondary cancers. The authors believe that raising the standards for Investigational New Drug (IND) approval and establishing a dynamic reporting and feedback system based on real-world data will strengthen regulatory oversight and support the sustainable growth of the CAR-T industry in China.

Direct mitochondrial import of lactate supports resilient carbohydrate oxidation.

Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using 13 C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/ Slc16a1 ). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.