Study on the sensitizing effect of SM-1 combined with irradiation on head and neck squamous cell carcinoma.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is globally prevalent with high recurrence, low survival rate, and poor quality of life for patients. Derived from PAC-1, SM-1 can activate procaspase-3 and induce apoptosis in cancer cells to exert anti-tumor effects. However, the inhibitory effect of SM-1 on HNSCC after combination with radiation are unclear. This study aims to investigate the radiosensitizing effect of SM-1 on HNSCC in vitro and in vivo. METHODS: MTT method was used to detect the effect of SM-1 on the viability of HNSCC cell lines (HONE1, HSC-2, and CAL27). The effects of SM-1 combined with radiation on the survival index of HONE1, HSC-2, and CAL27 cell lines were determined by colony formation assay. Flow cytometry was used to investigate the effects of SM-1 and radiation combination on cell apoptosis and cell cycle, and western blot experiments were performed to detect the expression of apoptosis and cell cycle-related proteins. Finally, a xenograft tumor model of CAL27 was established to evaluate the anti-tumor effect of SM-1 combined with radiation in vivo. RESULTS: In vitro, SM-1 effectively inhibited the activity of HNSCC cell lines HONE1, HSC-2, and CAL27 cells, and synergistically showed anti-proliferation activity during combined irradiation. Meanwhile, anti-tumor effect of SM-1 on HNSCC was higher than that of Debio1143, and the radiosensitivity of cells was greatly increased. Flow cytometry and western blot analysis showed that SM-1 induced G2/M phase arrest of head and neck squamous cell carcinoma cells via inhibiting the expression of CyclinB1 and CDC2. Moreover, SM-1 activated caspase-3 activity and up-regulated the cleaved form of PARP1 to induce cell apoptosis. In vivo, SM-1 combined irradiation showed a good anti-tumor effect. CONCLUSION: SM-1 enhances HNSCC cell radiation sensitivity in vitro and in vivo, supporting its potential as a radiosensitizer for clinical trials in combination with radiotherapy.

Fc receptor-like A promotes malignant behavior in renal cell carcinoma and correlates with tumor immune infiltration.

BACKGROUND: Our study aims to investigate the mechanisms through which Fc receptor-like A (FCRLA) promotes renal cell carcinoma (RCC) and to examine its significance in relation to tumor immune infiltration. MATERIALS AND METHODS: The correlation between FCRLA and data clinically related to RCC was explored using The Cancer Genome Atlas (TCGA), then validated using Gene Expression Omnibus (GEO) gene chip data. Enrichment and protein-protein interaction (PPI) network analyses were performed for FCRLA and its co-expressed genes. FCRLA was knocked down in RCC cell lines to evaluate its impact on biological behavior. Then the potential downstream regulators of FCRLA were determined by western blotting, and rescue experiments were performed for verification. The relevance between FCRLA and various immune cells was analyzed through GSEA, TIMER, and GEPIA tools. TIDE and ESTIMATE algorithms were used to predict the effect of FCRLA in immunotherapy. RESULTS: Fc receptor-like A was associated with clinical and T stages and could predict the M stage (AUC = 0.692) and 1-3- and 5-year survival rates (AUC = 0.823, 0.834, and 0.862) of RCC patients. Higher expression of FCLRA predicted an unfavorable overall survival (OS) in TCGA-RCC and GSE167573 datasets (p = 0.03, p = 0.04). FCRLA promoted the malignant biological behavior of RCC cells through the pERK1/2/-MMP2 pathway and was associated with tumor immune microenvironment in RCC. CONCLUSION: Fc receptor-like A is positively correlated with poor outcomes in RCC patients and plays an oncogenic role in RCC through the pERK1/2-MMP2 pathway. Patients with RCC might benefit from immunotherapy targeting FCRLA.

Altered Abdominal Muscle Recruitment and Declined Physical Function in Postpartum Individuals With Pregnancy-Related Pelvic Girdle Pain: A Matched Case-Control Study.

INTRODUCTION: The influence of pregnancy-related pelvic girdle pain (PPGP) on lumbopelvic muscles has not been comprehensively examined in postpartum individuals. Previous research also presented self-reported activity limitations without objective measures. METHODS: Thirty postpartum individuals with PPGP (PPGP group) and 30 age-, parity-, and postpartum duration-matched asymptomatic individuals (healthy group) were recruited. Transabdominal ultrasonography was used to measure muscle thickness or activation changes of the external oblique (EO), internal oblique (IO), transverse abdominals, lumbar multifidus, and pelvic floor muscles (PFMs) during rest and while performing the active straight leg raise (ASLR). Muscle changes were compared separately in the painful and nonpainful sides between the PPGP and health control group. Physical function was assessed using the ASLR fatigue (ASLRF), timed up-and-go, and 6-m walking (6MW) tests. RESULTS: The PPGP group had greater thickening changes in the bilateral IO during ASLR compared with the healthy group (nonpainful side, 16.34 vs 3.52 mm; P = .010; painful side, 18.83 vs 6.60 mm; P = .02) but became thinner in the EO (nonpainful side, -2.19 vs 19.97 mm; P < .001; painful side, -5.97 vs 21.43 mm; P < .001). Thicker IO and EO on the nonpainful side (IO, 6.60 vs 5.78 mm; P = .004; EO, 5.37 vs 4.54 mm; P = .011) and a lower bladder base (indication of PFMs) (91.87 vs 78.61 mm; P = .002) during rest were also observed in the PPGP group. Furthermore, the performance of the ASLRF and 6MW tests was poorer in the PPGP than in the healthy group (ASLRF nonpainful side, 82.36 vs 59.09 sec; P = .01; painful side, 75.73 vs 59.26 sec; P = .04; 6MW, 3.48 vs 3.17 sec; P = .02). DISCUSSION: Postpartum individuals with PPGP demonstrated altered abdominal muscle recruitment strategies during loading tasks, with objectively impaired physical functions. These findings are critical for developing effective muscle training interventions for PPGP.

Effectiveness of high-intensity focused ultrasound combined with gonadotropin-releasing hormone agonist or combined with levonorgestrel-releasing intrauterine system for adenomyosis: A systematic review and meta-analysis.

Gonadotropin-Releasing Hormone Agonist (GnRH-a) and levonorgestrel releasing intrauterine system (LNG-IUS) are conventional conservative treatments for adenomyosis, and high-intensity focused ultrasound (HIFU) is a novel ablation technique. This study aimed to investigate the effectiveness of HIFU combined with GnRH-a or LNG-IUS for adenomyosis patients. In this systematic review and meta-analysis, Pubmed, Embase, Cochrane Library and Scopus databases were searched up to December 2021. Published studies comparing HIFU plus GnRH-a with HIFU plus LNG-IUS in adenomyosis patients were assessed for eligibility by two independent authors. Risk of bias tool was utilized for risk evaluation. We selected treatment effective rate of dysmenorrhea (pain during menstruation) as the primary outcome; effective rate of menorrhagia severity and reduction rate of adenomyotic lesion as the secondary outcomes. Adverse effects were assessed. Four studies with a total 729 patients were enrolled in the meta-analysis. HIFU plus LNG-IUS showed lower dysmenorrhea [within 6 months: risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83-0.93, p < 0.00001; over 1 year: RR 0.73, 95% CI 0.65-0.82, p < 0.00001] and less menorrhagia severity (RR 0.63, 95% CI 0.60-0.66, p < 0.00001) than HIFU plus GnRH-a. Both groups demonstrated equal efficacy in adenomyotic lesion reduction rate (RR 1.03, 95% CI 0.97-1.09, p = 0.30). Adverse effects happened equally in both groups. Combination therapy of HIFU and LNG-IUS revealed better effectiveness in treating dysmenorrhea and menorrhagia than that of HIFU and GnRH-a. However, interpreting the conclusion should be approached with caution as a result of significant heterogeneity.

Arteriovenous malformation-related headache and seizures in pregnancy masquerading as eclampsia: A case report.

OBJECTIVE: Cerebral arteriovenous malformation during pregnancy is rare but lethal disease that usually present with new-onset seizures and headaches mimicking eclampsia. We report a rare case of cerebral arteriovenous malformation with abrupt seizures in the third trimester. CASE REPORT: A 28-year-old primipara was brought to our emergency department at 32 6/7 weeks of gestation with new-onset acute seizures and hypertension. Owing to neurological deterioration, the patient underwent emergency cesarean delivery. However, 24 h after cesarean delivery and eclampsia treatment, the seizures worsened. Computed tomography and magnetic resonance imaging showed unruptured arteriovenous malformation of the right frontal lobe. Subsequently, intraarterial embolization was performed. The patient was discharged 5 days after surgery without neurological sequelae or obstetric complications. CONCLUSION: This case report highlights the differential diagnoses of sudden new-onset seizures in late pregnancy for obstetricians and emergency medicine physicians. Lethal cerebral diseases, apart from eclampsia, should be considered during pregnancy.

Cervical cancer and risk of dementia: real-world insights from a nationwide cohort study in Taiwan.

OBJECTIVE: Cervical cancer, linked to human papillomavirus (HPV), ranks fourth among women's cancers globally. Several studies have found an association between viral infections or cancer and dementia, which is a major public health concern. This study aimed to provide real-world data on the association between cervical cancer and the risk of dementia. METHODS: This population-based cohort study, utilizing Taiwan's National Health Insurance Research Database, included 53 905 patients, with 10 781 having cervical cancer, matching with 43 124 controls in a 1:4 ratio based on age and indexed date. Incidence density rates were used to calculate the incidence rate of dementia. Adjusting for comorbidities, a multivariable Cox proportional hazards regression model was used to estimate the hazard ratios and 95% confidence intervals. Additionally, the risk of dementia was further verified using the cumulative incidence analyzed by the Kaplan-Meier method. RESULTS: This study indicated a significantly higher dementia risk in the cervical cancer cohort compared with the non-cervical cancer cohort (adjusted HR (aHR)=1.64, 95% CI 1.16 to 2.26; p<0.001), suggesting a 1.64-fold increased risk. Notably, cervical cancer posed a greater risk of dementia (aHR=1.69, 95% CI 1.21 to 2.29; p<0.001) compared with carcinoma in situ of the cervix (p=0.18) and cervical intraepithelial neoplasia (p=0.23). The cumulative incidence of dementia in the cervical cancer group was significantly higher (log-rank test, p<0.001) than the control group. CONCLUSIONS: Cervical cancer (invasive disease) was associated with a significant risk of dementia, unlike carcinoma in situ of the cervix and cervical intraepithelial neoplasia (pre-invasive diseases), suggesting HPV infections may play a role in dementia, particularly oncogenic types. This highlights the importance of further investigation into the underlying mechanisms of the association between cervical cancer and dementia.

Prognostic Significance of Phenylalanine in Heart Failure: Clinical Insights and Inter-Organ Crosstalk Snapshot.

Background: Heart failure (HF) remains a leading cause of morbidity and mortality globally, necessitating the identification of reliable prognostic biomarkers to guide therapeutic interventions. Recent clinical observations have underscored phenylalanine (PHE) as a prognostic marker in HF, although the mechanisms involving inter-organ crosstalk remain understood. Methods: This study adopted a dull approach, with a retrospective analysis of 550 HF patients to establish the prognostic value of pre-discharge PHE levels and a study on the inter-organ crosstalk of PHE among 24 patients. We analyzed the correlations between PHE concentrations and clinical outcomes, alongside a comprehensive examination of PHE metabolism across the skeletal muscle, liver, heart, kidney, and lung. Results: In the clinical prognostic analysis of 550 patients hospitalized for acute decompensated HF, elevated PHE levels (≥65.6 µM) were significantly and independently associated with increased all-cause mortality during a median follow-up of 4.5 years (log rank = 36.7, p < 0.001), underscoring its value as a prognostic marker in HF. The inter-organic crosstalk study elucidated the mechanism associated with PHE elevation in patients with HF, characterized by an increase in PHE output in skeletal muscle and a decrease in hepatic and cardiac PHE uptakes. Notably, PHE concentration gradients across these organs were correlated with HF severity, such as the NYHA functional class, B-type natriuretic peptide levels, and the presence of acute HF. Conclusions: Our findings confirm the prognostic significance of PHE in patients with HF and unveil the complex metabolic interplay among key organs that contribute to PHE dysregulation. These insights not only reinforce the importance of metabolic monitoring in HF management but also open avenues for therapeutic targets.

Propofol Mitigates Sepsis-Induced Brain Injury by Inhibiting Ferroptosis Via Activation of the Nrf2/HO-1axis.

BACKGROUND: Sepsis-associated encephalopathy (SAE) develops in 30-70% of hospitalized patients with sepsis. In intensive care units (ICUs), propofol is often administered to ensure an appropriate level of sedation in mechanically ventilated patients. Ferroptosis is a newly identified mode of cellular death characterized by the peroxidation of membrane lipids and excessive iron. This study was conducted to explore the interplay between propofol, sepsis, and ferroptosis. METHODS: An acute systemic inflammatory model was constructed via the intraperitoneal administration of lipopolysaccharide (LPS). Nissl and Fluoro-Jade C (FJC) staining were employed to display neuronal damage and degeneration. Western blotting and immunofluorescence (IF) staining of Bax and Bcl-2 were used to confirm the neural apoptosis. QPCR of cytokines and DHE staining were used to indicate neuroinflammation. To validate ferroptosis, we assessed the content of malondialdehyde (MDA), GSH, and tissue iron, accompanied by transcription level of CHAC1, PTGS2 and GPX4. Additionally, we examined the content of acyl-CoA synthetase long-chain family member 4 (ACSL4), xCT (SLC7A11, solute carrier family 7 member 11), and glutathione peroxidase 4 (GPX4). The IF staining of Iba1-labeled microglia and GFAP-marked astrocytes were used to measure the gliosis. Erastin was pre-pretreated to confirm the anti-ferroptotic capability of propofol. ML385 was preconditioned to explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in propofol-repressed ferroptosis. RESULTS: Propofol dose-dependently inhibited the decrease of Nissl-positive neurons and the increase of FJC-stained neurons in septic hippocampus and cortex. Neural cytokines, oxidative stress, apoptosis and gliosis were reduced by propofol. Propofol repressed the level of MDA, iron, CHAC1, PTGS2, ACLS4 and restored the content of GSH, GPX4, xCT, Nrf2 and HO-1, thus inhibiting sepsis-induced ferroptosis. All protections from propofol could be reversed by eratsin and ML385 pretreatment. CONCLUSION: Propofol protected against sepsis-induced brain damage, neuroinflammation, neuronal apoptosis and gliosis through the activation of the Nrf2/HO-1 axis to combat ferroptosis.

Transabdominal ultrasonography-guided biofeedback training for pelvic floor muscles integrated with stabilization exercise improved pregnancy-related pelvic girdle pain and disability: a randomized controlled trial.

OBJECTIVES: Investigate effects of integrated training for pelvic floor muscles (PFM) with and without transabdominal ultrasonography (TAUS) imaging-guided biofeedback in postpartum women with pregnancy-related pelvic girdle pain (PPGP). DESIGN: Three-arm, single-blinded randomized controlled trial SETTING: University laboratory PARTICIPANTS: Fifty-three postpartum women with PPGP randomized into stabilization exercise with TAUS-guided biofeedback (BIO+EXE), exercise (EXE), and control (CON) groups. INTERVENTIONS: The BIO+EXE and EXE groups underwent an 8-week exercise program, with the BIO+EXE group receiving additional TAUS-guided biofeedback for PFM training during the first 4 weeks. The CON group only received a pelvic educational session. MAIN OUTCOME MEASURES: Primary outcomes included self-reported pain (numeric rating scale) and disability (pelvic girdle questionnaire). Secondary outcomes included functional tests (active straight leg raising [ASLR] fatigue, timed up-and-go, and 6-meter walking tests) and muscle contractibility indicated by muscle thickness changes for abdominal muscles and bladder base displacement for PFM (ultrasonographic measures). RESULTS: The BIO+EXE group had lower pain [1.8 (1.5) vs. 4.4 (1.5), mean difference -2.6, 95% confidence interval (CI) -3.9 to -1.2] and disability [14% (10) vs. 28% (21), mean difference -14, 95% CI -25 to -2] and faster walking speed [3.1 seconds (1) vs. 3.3 seconds (1), mean difference -0.2, 95% CI -1.0 to -0.2] than the CON group. The EXE group only had lower pain intensity compared to the CON group [2.7 (2.0) vs. 4.4 (1.5), mean difference -1.7, 95% CI -3.1 to -0.4]. No significant differences were observed among groups in timed up-and-go, ASLR fatigue, or muscle contractibility. CONCLUSIONS: Integrated training for PFM and stabilization with TAUS-guided biofeedback seems to be beneficial for reducing pain and disability in postpartum women with PPGP. CONTRIBUTION OF THE PAPER.

LEUTX regulates porcine embryonic genome activation in somatic cell nuclear transfer embryos.

Emerging evidence highlights the regulatory role of paired-like (PRD-like) homeobox transcription factors (TFs) in embryonic genome activation (EGA). However, the majority of PRD-like genes are lost in rodents, thus prompting an investigation into PRD-like TFs in other mammals. Here, we showed that PRD-like TFs were transiently expressed during EGA in human, monkey, and porcine fertilized embryos, yet they exhibited inadequate expression in their cloned embryos. This study, using pig as the research model, identified LEUTX as a key PRD-like activator of porcine EGA through genomic profiling and found that LEUTX overexpression restored EGA failure and improved preimplantation development and cloning efficiency in porcine cloned embryos. Mechanistically, LEUTX opened EGA-related genomic regions and established histone acetylation via recruiting acetyltransferases p300 and KAT2A. These findings reveal the regulatory mechanism of LEUTX to govern EGA in pigs, which may provide valuable insights into the study of early embryo development for other non-rodent mammals.

Temporal landscape and translational regulation of A-to-I RNA editing in mouse retina development.

BACKGROUND: The significance of A-to-I RNA editing in nervous system development is widely recognized; however, its influence on retina development remains to be thoroughly understood. RESULTS: In this study, we performed RNA sequencing and ribosome profiling experiments on developing mouse retinas to characterize the temporal landscape of A-to-I editing. Our findings revealed temporal changes in A-to-I editing, with distinct editing patterns observed across different developmental stages. Further analysis showed the interplay between A-to-I editing and alternative splicing, with A-to-I editing influencing splicing efficiency and the quantity of splicing events. A-to-I editing held the potential to enhance translation diversity, but this came at the expense of reduced translational efficiency. When coupled with splicing, it could produce a coordinated effect on gene translation. CONCLUSIONS: Overall, this study presents a temporally resolved atlas of A-to-I editing, connecting its changes with the impact on alternative splicing and gene translation in retina development.

The PTM profiling of CTCF reveals the regulation of 3D chromatin structure by O-GlcNAcylation.

CCCTC-binding factor (CTCF), a ubiquitously expressed and highly conserved protein, is known to play a critical role in chromatin structure. Post-translational modifications (PTMs) diversify the functions of protein to regulate numerous cellular processes. However, the effects of PTMs on the genome-wide binding of CTCF and the organization of three-dimensional (3D) chromatin structure have not been fully understood. In this study, we uncovered the PTM profiling of CTCF and demonstrated that CTCF can be O-GlcNAcylated and arginine methylated. Functionally, we demonstrated that O-GlcNAcylation inhibits CTCF binding to chromatin. Meanwhile, deficiency of CTCF O-GlcNAcylation results in the disruption of loop domains and the alteration of chromatin loops associated with cellular development. Furthermore, the deficiency of CTCF O-GlcNAcylation increases the expression of developmental genes and negatively regulates maintenance and establishment of stem cell pluripotency. In conclusion, these results provide key insights into the role of PTMs for the 3D chromatin structure.

Ultrasonographic measurement indicated patients with chronic neck pain had reduced diaphragm thickness and mobility along with declined respiratory functions.

BACKGROUND: Chronic neck pain (CNP) is a prevalent musculoskeletal condition including notable impairments in respiratory function. The diaphragm, serving dual roles in respiration and spinal stability, is intricately linked to the cervical spine through fascial, neurophysiological, and biomechanical connections. However, to date, none has investigated the diaphragm function in patients with CNP. OBJECTIVES: To investigate the diaphragm function, respiratory muscle strength, and pulmonary function in patients with CNP. In addition, their associations were also examined. DESIGN: A case-control study. METHODS: A total of 54 participants were recruited including 25 patients with CNP (CNP group) and 29 healthy adults (CON group). Pulmonary function including forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), and respiratory muscle strength represented by maximal inspiratory (MIP) and maximal expiratory pressure (MEP), as well as diaphragm function including ultrasonographic measures of mobility and thickness changes during maximal inspiration and expiration were assessed in all participants. Additionally, the intensity of pain and disability were evaluated using a Visual Analog Scale and Neck Disability Index only in patients with CNP. RESULTS: Significant reductions of the FVC, FEV1, MIP, and MEP were found in the CNP group compared to the CON group (p < 0.05). The diaphragm mobility and thickness changes were also significantly decreased in the CNP group than the CON group with medium effect sizes (p < 0.05). Only diaphragm thickness change was positively correlated with FVC, FEV1, and MEP in patients with CNP. Furthermore, MEP showed the strongest contribution to diaphragm thickness change based on the regression analysis. CONCLUSIONS: Impaired diaphragm function, respiratory muscle strength, and pulmonary function were observed in patients with CNP. Patients with smaller diaphragm thickness change had poorer pulmonary function and reduced maximal expiratory muscle strength. Diaphragm assessment and intervention may be considered in CNP management.

Propofol and Dexmedetomidine Ameliorate Endotoxemia-Associated Encephalopathy via Inhibiting Ferroptosis.

Background: Sepsis is recognized as a multiorgan and systemic damage caused by dysregulated host response to infection. Its acute systemic inflammatory response highly resembles that of lipopolysaccharide (LPS)-induced endotoxemia. Propofol and dexmedetomidine are two commonly used sedatives for mechanical ventilation in critically ill patients and have been reported to alleviate cognitive impairment in many diseases. In this study, we aimed to explore and compare the effects of propofol and dexmedetomidine on the encephalopathy induced by endotoxemia and to investigate whether ferroptosis is involved, finally providing experimental evidence for multi-drug combination in septic sedation. Methods: A total of 218 C57BL/6J male mice (20-25 g, 6-8 weeks) were used. Morris water maze (MWM) tests were performed to evaluate whether propofol and dexmedetomidine attenuated LPS-induced cognitive deficits. Brain injury was evaluated using Nissl and Fluoro-Jade C (FJC) staining. Neuroinflammation was assessed by dihydroethidium (DHE) and DCFH-DA staining and by measuring the levels of three cytokines. The number of Iba1+ and GFAP+ cells was used to detect the activation of microglia and astrocytes. To explore the involvement of ferroptosis, the levels of ptgs2 and chac1; the content of iron, malondialdehyde (MDA), and glutathione (GSH); and the expression of ferroptosis-related proteins were investigated. Conclusion: The single use of propofol and dexmedetomidine mitigated LPS-induced cognitive impairment, while the combination showed poor performance. In alleviating endotoxemic neural loss and degeneration, the united sedative group exhibited the most potent capability. Both propofol and dexmedetomidine inhibited neuroinflammation, while propofol's effect was slightly weaker. All sedative groups reduced the neural apoptosis, inhibited the activation of microglia and astrocytes, and relieved neurologic ferroptosis. The combined group was most prominent in combating genetic and biochemical alterations of ferroptosis. Fpn1 may be at the core of endotoxemia-related ferroptosis activation.

Prediction of Clinical Response to Dupilumab in Patients with Severe Asthma Using Fractional Exhaled Nitric Oxide Combined with Pulmonary Function Testing.

INTRODUCTION: This study aimed to assess the effectiveness of fractional exhaled nitric oxide (FeNO) combined with pulmonary function testing (PFT) for predicting the treatment outcome of patients with severe asthma receiving dupilumab. METHODS: A total of 31 patients with severe asthma visiting our hospital from January 2022 to June 2023 were included in this study, with 28 patients completing a 16-week course of dupilumab treatment. Baseline clinical data, including demographic information, blood eosinophil counts, serum IgE levels, FeNO, asthma control test (ACT), asthma control questionnaire (ACQ), and other parameters, were collected. A predictive model using a generalized linear model was established. RESULTS: Following the 16-week course of dupilumab treatment, 22 patients showed effective response based on GETE scores, while 6 patients were nonresponders. Notably, significant improvements were observed in clinical parameters such as blood eosinophil counts, serum IgE levels, FeNO, FEV1, FEV1%, ACT, and ACQ in both response groups (p < 0.05). FeNO and pulmonary function tests demonstrated AUC values of 0.530, 0.561, and 0.765, respectively, in predicting the clinical efficacy of dupilumab, which were lower than when FeNO was combined with FEV1%. The combination of FeNO and FEV1% had a sensitivity of 1.000 and specificity of 0.591 in predicting treatment response. CONCLUSION: The combined assessment of FeNO and FEV1% provides improved accuracy for predicting the clinical efficacy of dupilumab in managing severe asthma. However, further larger scale clinical studies with comprehensive follow-up data are needed to validate the therapeutic efficacy and applicability across diverse patient populations.

2024 Guidelines of the Taiwan Society of Cardiology for the Diagnosis and Treatment of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a multi-organ systemic syndrome that involves cardiac and extra-cardiac pathophysiological abnormalities. Its growing prevalence causes a major public concern worldwide. HFpEF is usually associated with multiple comorbidities, and non-cardiovascular death is common in patients with HFpEF. In Asia, patients with HFpEF has a younger age, higher prevalence of diabetes and chronic kidney disease than Western countries. A 2-step diagnostic algorithm is recommended in this guideline. In the first step, the diagnosis of HFpEF can be made if patients have symptoms and/or signs of heart failure, left ventricular ejection fraction ≥ 50%, increased natriuretic peptide, and objective evidence of left atrial or left ventricular abnormalities or raised left ventricular filling pressure. If diagnosis is still uncertain, invasive or noninvasive stress test can be performed in the second step. Comorbidities need to be controlled in HFpEF. Weight reduction for obesity and supervised exercise training are recommended for HFpEF. For pharmacological therapy, diuretic is used to relieve congestion and sodium-glucose cotransporter 2 inhibitor, empagliflozin or dapagliflozin, is recommended to improve prognosis of HFpEF. The research on HFpEF is advancing at a rapid pace. It is expected that newer modalities for diagnosis and management of HFpEF could appear in the near future.

Concurrent Atezolizumab Plus Bevacizumab and High-Dose External Beam Radiotherapy for Highly Advanced Hepatocellular Carcinoma.

BACKGROUND: Atezolizumab plus bevacizumab (atezo-bev) has been recommended for advanced hepatocellular carcinoma (HCC). High-dose external beam radiotherapy (RT) is recognized for its excellent local tumor control. The efficacy and safety of concurrent atezo-bev with RT for highly advanced HCC has been minimally explored. METHODS: In this preliminary retrospective study, we assessed patients with highly advanced HCC, characterized by Vp4 portal vein thrombosis or tumors exceeding 50% of liver volume, who received concurrent atezo-bev and RT (group A). Group A included 13 patients who received proton radiation at a dose of 72.6 GyE in 22 fractions, and one patient who received photon radiation at a dose of 54 Gy in 18 fractions. This group was compared with 34 similar patients treated atezo-bev alone as a control (group B). The primary objectives were to evaluate the objective response rate (ORR), overall survival (OS), and safety. RESULTS: Baseline characteristics were similar between groups, except for a higher incidence of Vp4 portal vein thrombosis in group A (78.6% vs. 21.4%, P = .05). Group A achieved a higher ORR (50.0% vs. 11.8%, P < .01) and a longer OS (not reached vs. 5.5 months, P = .01) after a median follow-up of 5.2 months. Multivariate analysis indicated that concurrent RT independently favored longer OS (hazard ratio: 0.18; 95% CI, 0.05-0.63, P < .01). Group A did not increase any grade adverse events (78.6% vs. 58.8%, P = .19) or severe adverse events of grade ≥ 3 (14.3% vs. 14.7%, P = .97) compared to group B. CONCLUSIONS: The concurrent high-dose external beam radiotherapy appears to safely enhance the effectiveness of atezolizumab plus bevacizumab for highly advanced patients with HCC. Further studies are warranted to confirm these findings.

A developmental validation of the Quick TargSeq 1.0 integrated system for automated DNA genotyping in forensic science for reference samples.

Analysis of short tandem repeats (STRs) is a global standard method for human identification. Insertion/Deletion polymorphisms (DIPs) can be used for biogeographical ancestry inference. Current DNA typing involves a trained forensic worker operating several specialized instruments in a controlled laboratory environment, which takes 6-8 h. We developed the Quick TargSeq 1.0 integrated system (hereinafter abbreviated to Quick TargSeq) for automated generation of STR and DIP profiles from buccal swab samples and blood stains. The system fully integrates the processes of DNA extraction, polymerase chain reaction (PCR) amplification, and electrophoresis separation using microfluidic biochip technology. Internal validation studies were performed using RTyper 21 or DIP 38 chip cartridges with single-source reference samples according to the Scientific Working Group for DNA Analysis Methods guidelines. These results indicated that the Quick TargSeq system can process reference samples and generate STR or DIP profiles in approximately 2 h, and the profiles were concordant with those determined using traditional STR or DIP analysis methods. Thus, reproducible and concordant DNA profiles were obtained from reference samples. Throughout the study, no lane-to-lane or run-to-run contamination was observed. The Quick TargSeq system produced full profiles from buccal swabs with at least eight swipes, dried blood spot cards with two 2-mm disks, or 10 ng of purified DNA. Potential PCR inhibitors (i.e., coffee, smoking tobacco, and chewing tobacco) did not appear to affect the amplification reactions of the instrument. The overall success rate and concordance rate of 153 samples were 94.12% and 93.44%, respectively, which is comparable to other commercially available rapid DNA instruments. A blind test initiated by a DNA expert group showed that the system can correctly produce DNA profiles with 97.29% genotype concordance with standard bench-processing methods, and the profiles can be uploaded into the national DNA database. These results demonstrated that the Quick TargSeq system can rapidly generate reliable DNA profiles in an automated manner and has the potential for use in the field and forensic laboratories.