iDVEIP: A computer-aided approach for the prediction of viral entry inhibitory peptides.

With the notable surge in therapeutic peptide development, various peptides have emerged as potential agents against virus-induced diseases. Viral entry inhibitory peptides (VEIPs), a subset of antiviral peptides (AVPs), offer a promising avenue as entry inhibitors (EIs) with distinct advantages over chemical counterparts. Despite this, a comprehensive analytical platform for characterizing these peptides and their effectiveness in blocking viral entry remains lacking. In this study, we introduce a groundbreaking in silico approach that leverages bioinformatics analysis and machine learning to characterize and identify novel VEIPs. Cross-validation results demonstrate the efficacy of a model combining sequence-based features in predicting VEIPs with high accuracy, validated through independent testing. Additionally, an EI type model has been developed to distinguish peptides specifically acting as Eis from AVPs with alternative activities. Notably, we present iDVEIP, a web-based tool accessible at http://mer.hc.mmh.org.tw/iDVEIP/, designed for automatic analysis and prediction of VEIPs. Emphasizing its capabilities, the tool facilitates comprehensive analyses of peptide characteristics, providing detailed amino acid composition data for each prediction. Furthermore, we showcase the tool's utility in identifying EIs against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

Single-Cell Secretion Analysis via Microfluidic Cell Membrane Immunosorbent Assay for Immune Profiling.

Single-cell multiplexed phenotypic analysis expands the biomarkers for diagnosis, heralding a new era of precision medicine. Cell secretions are the primary measures of immune function, but single-cell screening remains challenging. Here, a novel cell membrane-based assay was developed using cholesterol-linked antibodies (CLAbs), integrating immunosorbent assays and droplet microfluidics to develop a flexible high-throughput single-cell secretion assay for multiplexed phenotyping. CLAb-grafted single cells were encapsulated in water-in-oil droplets to capture their own secretions. Subsequently, the cells were extracted from droplets for fluorescence labeling and screening. Multiple secretions and surface proteins were simultaneously measured from single cells by flow cytometry. To validate the approach, THP-1 cells, THP-1-derived M1 macrophages, and dendritic cells were assayed, indicating the differentiation efficiency of THP-1 cells under different chemical stimulations. Moreover, peripheral blood mononuclear cells from healthy donors under various stimuli showed varied active immune cell populations (6.62-47.14%). The peripheral blood mononuclear cells (PBMCs) of nasopharyngeal carcinoma patients were analyzed to identify a higher percentage of actively cytokine-secreted single cells in the basal state (2.82 ± 1.48%), compared with that in the health donors (0.70 ± 0.29%).

iDVIP: identification and characterization of viral integrase inhibitory peptides.

Antiretroviral peptides are a kind of bioactive peptides that present inhibitory activity against retroviruses through various mechanisms. Among them, viral integrase inhibitory peptides (VINIPs) are a class of antiretroviral peptides that have the ability to block the action of integrase proteins, which is essential for retroviral replication. As the number of experimentally verified bioactive peptides has increased significantly, the lack of in silico machine learning approaches can effectively predict the peptides with the integrase inhibitory activity. Here, we have developed the first prediction model for identifying the novel VINIPs using the sequence characteristics, and the hybrid feature set was considered to improve the predictive ability. The performance was evaluated by 5-fold cross-validation based on the training dataset, and the result indicates the proposed model is capable of predicting the VINIPs, with a sensitivity of 85.82%, a specificity of 88.81%, an accuracy of 88.37%, a balanced accuracy of 87.32% and a Matthews correlation coefficient value of 0.64. Most importantly, the model also consistently provides effective performance in independent testing. To sum up, we propose the first computational approach for identifying and characterizing the VINIPs, which can be considered novel antiretroviral therapy agents. Ultimately, to facilitate further research and development, iDVIP, an automatic computational tool that predicts the VINIPs has been developed, which is now freely available at http://mer.hc.mmh.org.tw/iDVIP/.

The difference between dacomitinib and afatinib in effectiveness and safety in first-line treatment of patients with advanced EGFR-mutant non-small cell lung cancer: a real-world observational study.

OBJECTIVES: The irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) afatinib and dacomitinib are approved for first-line treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and dacomitinib in this setting. MATERIALS AND METHODS: Between September 2020 and March 2023, we retrospectively recruited patients diagnosed with advanced-stage EGFR-mutant NSCLC who were treated with first-line irreversible EGFR-TKIs. The enrolled patients were assigned to two groups based on whether they received afatinib or dacomitinib. RESULTS: A total of 101 patients were enrolled in the study (70 to afatinib and 31 to dacomitinib). The partial response rates (PR) for first-line treatment with afatinib and dacomitinib were 85.7 and 80.6% (p = 0.522). The median progression-free survival (PFS) (18.9 vs. 16.3 months, p = 0.975) and time to treatment failure (TTF) (22.7 vs. 15.9 months, p = 0.324) in patients with afatinib and dacomitinib treatment were similar. There was no significant difference observed in the median PFS (16.1 vs. 18.9 months, p = 0.361) and TTF (32.5 vs. 19.6 months, p = 0.182) between patients receiving the standard dose and those receiving the reduced dose. In terms of side effects, the incidence of diarrhea was higher in the afatinib group (75.8% vs. 35.5%, p < 0.001), while the incidence of paronychia was higher in the dacomitinib group (58.1% vs. 31.4%, p = 0.004). The PFS (17.6 vs. 24.9 months, p = 0.663) and TTF (21.3 vs. 25.1 months, p = 0.152) were similar between patients younger than 75 years and those older than 75 years. CONCLUSION: This study showed that afatinib and dacomitinib had similar effectiveness and safety profiles. However, they have slightly different side effects. Afatinib and dacomitinib can be safely administered to patients across different age groups with appropriate dose reductions.

Laparoscopic training workshop to assess medical students' skill acquisition and interest in surgical careers.

BACKGROUND: With its minimally invasive approach, laparoscopic surgery has transformed the medical landscape. As the demand for these procedures escalates, there is a pressing need for adept surgeons trained in laparoscopic techniques. However, current training often falls short of catering to medical school education. This study evaluates the impact of a custom-designed laparoscopic training workshop on medical students' surgical skills and career aspirations. METHODS: This prospective experimental study was conducted at the E-Da hospital in Kaohsiung City, Taiwan. Medical students from Taiwanese medical schools undergoing Clerk 5, Clerk 6, and Postgraduate Year 1 and 2 were invited to participate. Medical students (n = 44) underwent an endoscopic skill training workshop consisting of lectures, box training, and live tissue training. The trainees performed multiple tasks before and after training using our objective evaluation system. The primary outcome was assessed before and after training through a questionnaire assessing the influence of training on students' interest in surgery as a career. The secondary outcome measured improvement in skill acquisition, comparing the task completion time pre- and post-workshop. For the primary outcome, descriptive statistics were used to summarize the questionnaire responses, and paired t-tests were performed to determine significant changes in interest levels post-workshop. For the secondary outcome, paired t-tests were used to compare the time recorded pre- and post-training. RESULTS: Post-training, participants exhibited significant proficiency gains, with task completion times reducing notably: 97 s (p = 0.0015) for Precision Beads Placement, 88.5 s (p < 0.0001) for Beads Transfer Exercise, 95 s (p < 0.0001) for Precision Balloon Cutting, and 137.8 s (p < 0.0001) for Intracorporeal Suture. The primary outcome showcased an increased mean score from 8.15 pre-workshop to 9.3 post-workshop, indicating a bolstered interest in surgery as a career. Additionally, post-training sentiment analysis underscored a predominant inclination toward surgery among 88% of participants. CONCLUSION: The custom-designed laparoscopic workshop significantly improved technical skills and positively influenced students' career aspirations toward surgery. Such hands-on training workshops can play a crucial role in medical education, bridging the gap between theoretical knowledge and practical skills and potentially shaping the future of budding medical professionals.

A real-world study comparing perioperative chemotherapy and EGFR-tyrosine kinase inhibitors for treatment of resected stage III EGFR-mutant adenocarcinoma.

BACKGROUND: The patient population with stage III non-small-cell lung cancer (NSCLC) is heterogeneous, with varying staging characteristics and diverse treatment options. Despite the potential practice-changing implications of randomized controlled trials evaluating the efficacy of perioperative epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), concerns have been raised due to conflicting overall survival (OS) results. Few real-world studies have examined the survival outcomes of patients with resected EGFR-mutant stage III adenocarcinoma receiving perioperative chemotherapy and EGFR-TKIs. METHODS: In this retrospective observational study, we enrolled patients with resected stage III adenocarcinoma with EGFR mutations between January 2011 and December 2021. Patients were classified into two groups: perioperative chemotherapy and perioperative EGFR-TKIs. Outcomes and prognostic factors were analyzed using Cox proportional hazards regression analysis. RESULTS: Eighty-four patients were enrolled in the analysis. Perioperative EGFR-TKIs led to longer progression-free survival (PFS) than chemotherapy (38.6 versus 14.2 months; p = 0.019). However, only pathological risk factors predicted poor PFS in multivariate analysis. Patients receiving perioperative chemotherapy had longer OS than those receiving EGFR-TKIs (111.3 versus 50.2 months; p = 0.052). Multivariate analysis identified perioperative treatment with EGFR-TKIs as an independent predictor of poor OS (HR: 3.76; 95% CI: 1.22-11.54). CONCLUSION: Our study demonstrates that chemotherapy should be considered in the perioperative setting for high-risk patients, when taking pathological risk factors into consideration, and that optimized sequencing of EGFR-TKIs might be the most critical determinant of OS.

Application of impulse oscillometry to detect interstitial lung disease and airway disease in adults with rheumatoid arthritis.

BACKGROUND: We conducted a retrospective observational study to explore the potential application of impulse oscillometry (IOS) as an alternative to high-resolution computed tomography (HRCT) for detecting pulmonary involvement in patients with rheumatoid arthritis (RA) because clinically evident interstitial lung disease (ILD) and airway involvement are common in this population. METHODS: We enrolled 72 patients with RA who underwent pulmonary function tests (PFTs) and IOS between September 2021 and September 2022. We aimed to identify the PFT and IOS variables associated with lung diseases shown on HRCT images. RESULTS: In our cohort of 72 patients, 48 underwent HRCT; of these, 35 had airway disease or ILD and 13 showed no obvious abnormalities on HRCT. Abnormal IOS and PFT parameters were observed in 34 and 23 patients, respectively, with abnormal HRCT images. The predicted percentages for forced vital capacity, the ratio of forced expiratory volume in the first one second to forced vital capacity, and forced mid-expiratory flow value were significantly lower in patients with abnormal HRCT. Lung resistance at 5 Hz, difference in resistance between 5 and 20 Hz, resonant frequency (Fres), and reactance area were higher in these patients and reactance at 5 Hz was lower. Compared to other parameters, Fres > 14.14 was significantly associated with alterations in HRCT and may be used as an indicator for monitoring disease. CONCLUSION: Fres > 14.14 is significantly associated with lung involvement in RA patients. Performance of spirometry with IOS is more beneficial than spirometry alone for evaluating lung involvement in RA patients.

Transdermal nanolipoplex simultaneously inhibits subcutaneous melanoma growth and suppresses systemically metastatic melanoma by activating host immunity.

Benefit for clinical melanoma treatments, the transdermal neoadjuvant therapy could reduce surgery region and increase immunotherapy efficacy. Using lipoplex (Lipo-PEG-PEI-complex, LPPC) encapsulated doxorubicin (DOX) and carrying CpG oligodeoxynucleotide; the transdermally administered nano-liposomal drug complex (LPPC-DOX-CpG) would have high cytotoxicity and immunostimulatory activity to suppress systemic metastasis of melanoma. LPPC-DOX-CpG dramatically suppressed subcutaneous melanoma growth by inducing tumor cell apoptosis and recruiting immune cells into the tumor area. Animal studies further showed that the colonization and growth of spontaneously metastatic melanoma cells in the liver and lung were suppressed by transdermal LPPC-DOX-CpG. Furthermore, NGS analysis revealed IFN-γ and NF-κB pathways were triggered to recruit and activate the antigen-presenting-cells and effecter cells, which could activate the anti-tumor responses as the major mechanism responsible for the therapeutic effect of LPPC-DOX-CpG. Finally, we have successfully proved transdermal LPPC-DOX-CpG as a promising penetrative carrier to activate systemic anti-tumor immunity against subcutaneous and metastatic tumor.

Flexible Seven-in-One Microsensor Embedded in High-Pressure Proton Exchange Membrane Water Electrolyzer for Real-Time Microscopic Monitoring.

The voltage, current, temperature, humidity, pressure, flow, and hydrogen in the high-pressure proton exchange membrane water electrolyzer (PEMWE) can influence its performance and life. For example, if the temperature is too low to reach the working temperature of the membrane electrode assembly (MEA), the performance of the high-pressure PEMWE cannot be enhanced. However, if the temperature is too high, the MEA may be damaged. In this study, the micro-electro-mechanical systems (MEMS) technology was used to innovate and develop a high-pressure-resistant flexible seven-in-one (voltage, current, temperature, humidity, pressure, flow, and hydrogen) microsensor. It was embedded in the upstream, midstream, and downstream of the anode and cathode of the high-pressure PEMWE and the MEA for the real-time microscopic monitoring of internal data. The aging or damage of the high-pressure PEMWE was observed through the changes in the voltage, current, humidity, and flow data. The over-etching phenomenon was likely to occur when this research team used wet etching to make microsensors. The back-end circuit integration was unlikely to be normalized. Therefore, this study used lift-off process to further stabilize the quality of the microsensor. In addition, the PEMWE is more prone to aging and damage under high pressure, so its material selection is very important.

Long-Acting Real-Time Microscopic Monitoring Inside the Proton Exchange Membrane Water Electrolyzer.

The proton exchange membrane water electrolyzer (PEMWE) requires a high operating voltage for hydrogen production to accelerate the decomposition of hydrogen molecules so that the PEMWE ages or fails. According to the prior findings of this R&D team, temperature and voltage can influence the performance or aging of PEMWE. As the PEMWE ages inside, the nonuniform flow distribution results in large temperature differences, current density drops, and runner plate corrosion. The mechanical stress and thermal stress resulting from pressure distribution nonuniformity will induce the local aging or failure of PEMWE. The authors of this study used gold etchant for etching, and acetone was used for the lift-off part. The wet etching method has the risk of over-etching, and the cost of the etching solution is also higher than that of acetone. Therefore, the authors of this experiment adopted a lift-off process. Using the flexible seven-in-one (voltage, current, temperature, humidity, flow, pressure, oxygen) microsensor developed by our team, after optimized design, fabrication, and reliability testing, it was embedded in PEMWE for 200 h. The results of our accelerated aging test prove that these physical factors affect the aging of PEMWE.

l-lactic acidosis confers insensitivity to PKC inhibitors by competing for uptake via monocarboxylate transporters.

Targeting protein kinase C (PKC) family was found to repress the migration and resistance of non-small cell lung cancer cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, none of the PKC inhibitors has been approved for anticancer therapy yet due to the limited efficacy in clinical trials, and the underlying mechanisms remain unclear. l-lactic acidosis, a common condition comprising high l-lactate concentration and acidic pH in the tumor microenvironment, has been known to induce tumor metastasis and drug resistance. In this study, l-lactic acid was found to reverse the inhibitory effects of pan-PKC inhibitors GO6983 on PKC activity, cell migration, and EGFR-TKI resistance, but these effects were not affected by the modulators of lactate receptor GPR81. Interestingly, blockade of lactate transporters, monocarboxylate transporter-1 and -4 (MCT1 and MCT4), attenuated the intracellular level of GO6983, and its inhibitory effect on PKC activity, suggesting that lactic acid promotes the resistance to PKC inhibitors by competing for the uptake through these transporters rather than by activating its receptor, GPR81. Our findings explain the underlying mechanisms of the limited response of PKC inhibitors in clinical trials.

When to add anti-angiogenesis drugs to EGFR-mutated metastatic non-small cell lung cancer patients: a real-world study from Taiwan.

BACKGROUND: The addition of anti-angiogenesis drugs to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) or chemotherapy in patients with EGFR-mutant non-small cell lung cancer (NSCLC) can improve disease control. We conducted a study to evaluate the efficacy of combination therapeutic strategies and identify patients who could benefit from combination therapy. METHODS: This study enrolled patients with stage IV EGFR-mutant NSCLC treated with first-line EGFR-TKIs between January 2014 and December 2020. We divided patients into three groups: patients who received an anti-angiogenesis drug as first-line combination therapy, those who received an anti-angiogenesis drug as further-line combination therapy, and those with no anti-angiogenesis therapy. RESULTS: A total of 204 patients were enrolled in the final analysis. Progression-free survival (PFS) in patients receiving first-line anti-angiogenesis plus EGFR-TKI combination therapy was longer (18.2 months) than those treated with first-line EGFR-TKI monotherapy (10.0 months for both, p < 0.001). No difference in overall survival (OS) was observed among these three groups (30.5 vs. 42.6 vs. 33.7 months, p = 0.326). Multivariate Cox regression analysis revealed L858R mutation, pleural, liver, and bone metastasis as independent prognostic factors for poor OS. However, the addition of anti-angiogenesis therapy to patients with these poor prognostic factors improved OS to levels similar to those without these poor prognostic factors. CONCLUSION: First-line combination EGFR-TKI plus anti-angiogenesis therapy improves PFS in patients with stage IV EGFR-mutant NSCLC. Adding an anti-angiogenesis drug at any line to patients harboring L858R mutation with pleural, liver, or bone metastases can provide survival benefits.

Anticancer peptide Q7 suppresses the growth and migration of human endometrial cancer by inhibiting DHCR24 expression and modulating the AKT-mediated pathway.

Endometrial cancer is one of the most common malignancy affecting women in developed countries. Resection uterus or lesion area is usually the first option for a simple and efficient therapy. Therefore, it is necessary to find a new therapeutic drug to reduce surgery areas to preserve fertility. Anticancer peptides (ACP) are bioactive amino acids with lower toxicity and higher specificity than chemical drugs. This study is to address an ACP, herein named Q7, which could downregulate 24-Dehydrocholesterol Reductase (DHCR24) to disrupt lipid rafts formation, and sequentially affect the AKT signal pathway of HEC-1-A cells to suppress their tumorigenicity such as proliferation and migration. Moreover, lipo-PEI-PEG-complex (LPPC) was used to enhance Q7 anticancer activity in vitro and efficiently show its effects on HEC-1-A cells. Furthermore, LPPC-Q7 exhibited a synergistic effect in combination with doxorubicin or paclitaxel. To summarize, Q7 was firstly proved to exhibit an anticancer effect on endometrial cancer cells and combined with LPPC efficiently improved the cytotoxicity of Q7.

Chondromalacia patella increases the risk of herpes zoster: a population-based study.

BACKGROUND: The reactivation of herpes zoster (HZ) is associated with disease stress. However, the relationship between chondromalacia patella (CMP) and HZ remains poorly understood. This study investigated the relationship between CMP and the risk of developing HZ. METHODS: Data were collected from the Taiwan's National Health Insurance Research Database. Patients with CMP diagnosed between 2000 and 2017 were assigned to the case group; patients without CMP were randomly selected from the same database and paired with controls matched by age and sex. The primary outcome was a diagnosis of HZ. All patients were followed until their diagnosis of HZ, their withdrawal from the NHI program, their death, or the end of 2017, whichever was earliest. The risk of developing HZ was compared between the case and control groups. RESULTS: In total, 22,710 patients with CMP and 90,840 matched controls were enrolled. The overall incidence rates of HZ in the CMP and control cohorts were 7.94 and 7.35 per 1,000 person-years, respectively. After potential confounders were controlled for, the case group exhibited a higher risk of HZ than did the control group [adjusted hazard ratio (aHR) = 1.06, p < 0.05]. In a stratification analysis by age, patients over 65 years old in the CMP group exhibited a higher risk of HZ than did those in the control group (aHR = 1.22, p < 0.01). In a stratification analysis by sex, women with CMP were at greater risk of developing HZ than women without CMP (aHR = 1.18, p < 0.01). CONCLUSION: Patients with CMP, especially elder adults and women, exhibited a higher risk of HZ. The HZ risk of patients with CMP should thus be assessed, and the necessity of HZ vaccination should be informed.

Percutaneous transluminal angioplasty and stenting of post-irradiated stenosis of subclavian artery.

BACKGROUND/PURPOSE: The therapeutic efficacy of percutaneous transluminal angioplasty and stenting (PTAS) of post-irradiated stenosis of subclavian artery (PISSA) was not well clarified. This retrospective study was designed to evaluate the technical safety and outcome of the patients of severe symptomatic PISSA accepted PTAS. METHODS: Between 2000 and 2019, 16 cases with 17 lesions of symptomatic and medically refractory PISSA accepted PTAS were included. We evaluated their technical success, peri-procedural complications and diffusion-weight imaging (DWI) of brain magnetic resonance imaging (MRI), results of symptom relief, and long-term stent patency. RESULTS: The stenosis of the 17 stenotic lesions were 81.2 ± 11.1%. The most common symptom of the 16 patients was dizziness (14/16, 87.5%). All successfully accepted PTAS without neurological complication and had symptom relief after PTAS (17/17, 100%). Of the 12 patients accepted pre-procedural and early post-procedural MRI follow-up, 2 patients had an asymptomatic tiny acute embolic infarct in the territory of vertebrobasilar system. In a 51.9 ± 54.9 months follow-up, all patients had no severe restenosis and no recurrent vertebrobasilar ischemic symptoms. CONCLUSION: For patients with PISSA and medically refractory ischemic symptoms, PTAS can be an effective alternative management.

Origami-Inspired Structure with Pneumatic-Induced Variable Stiffness for Multi-DOF Force-Sensing.

With the emerging need for human-machine interactions, multi-modal sensory interaction is gradually pursued rather than satisfying common perception forms (visual or auditory), so developing flexible, adaptive, and stiffness-variable force-sensing devices is the key to further promoting human-machine fusion. However, current sensor sensitivity is fixed and nonadjustable after fabrication, limiting further development. To solve this problem, we propose an origami-inspired structure to achieve multiple degrees of freedom (DoFs) motions with variable stiffness for force-sensing, which combines the ductility and flexibility of origami structures. In combination with the pneumatic actuation, the structure can achieve and adapt the compression, pitch, roll, diagonal, and array motions (five motion modes), which significantly increase the force adaptability and sensing diversity. To achieve closed-loop control and avoid excessive gas injection, the ultra-flexible microfiber sensor is designed and seamlessly embedded with an approximately linear sensitivity of ∼0.35 Ω/kPa at a relative pressure of 0-100 kPa, and an exponential sensitivity at a relative pressure of 100-350 kPa, which can render this device capable of working under various conditions. The final calibration experiment demonstrates that the pre-pressure value can affect the sensor's sensitivity. With the increasing pre-pressure of 65-95 kPa, the average sensitivity curve shifts rightwards around 9 N intervals, which highly increases the force-sensing capability towards the range of 0-2 N. When the pre-pressure is at the relatively extreme air pressure of 100 kPa, the force sensitivity value is around 11.6 Ω/N. Therefore, our proposed design (which has a low fabrication cost, high integration level, and a suitable sensing range) shows great potential for applications in flexible force-sensing development.

miR-221 confers lapatinib resistance by negatively regulating p27kip1 in HER2-positive breast cancer.

Development of acquired resistance to lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor, severely limits the duration of clinical response in advanced HER2-driven breast cancer patients. Although the compensatory activation of the PI3K/Akt survival signal has been proposed to cause acquired lapatinib resistance, comprehensive molecular mechanisms remain required to develop more efficient strategies to circumvent this therapeutic difficulty. In this study, we found that suppression of HER2 by lapatinib still led to Akt inactivation and elevation of FOX3a protein levels, but failed to induce the expression of their downstream pro-apoptotic effector p27kip1 , a cyclin-dependent kinase inhibitor. Elevation of miR-221 was found to contribute to the development of acquired lapatinib resistance by targeting p27kip1 expression. Furthermore, upregulation of miR-221 was mediated by the lapatinib-induced Src family tyrosine kinase and subsequent NF-κB activation. The reversal of miR-221 upregulation and p27kip1 downregulation by a Src inhibitor, dasatinib, can overcome lapatinib resistance. Our study not only identified miRNA-221 as a pivotal factor conferring the acquired resistance of HER2-positive breast cancer cells to lapatinib through negatively regulating p27kip1 expression, but also suggested Src inhibition as a potential strategy to overcome lapatinib resistance.

Multiplexed Single-Cell Leukocyte Enzymatic Secretion Profiling from Whole Blood Reveals Patient-Specific Immune Signature.

Enzymatic secretion of immune cells (leukocytes) plays a dominant role in host immune responses to a myriad of biological triggers, including infections, cancers, and cardiovascular diseases. Current tools to probe these leukocytes inadequately profile these vital biomarkers; the need for sample preprocessing steps of cell lysis, labeling, washing, and pipetting inevitably triggers the cells, changes its basal state, and dilutes the individual cell secretion in bulk assays. Using a fully integrated system for multiplexed profiling of native immune single-cell enzyme secretion from 50 µL of undiluted blood, we eliminate sample handling. With a total analysis time of 60 min, the integrated platform performs six tasks of leukocyte extraction, cell washing, fluorescent enzyme substrate mixing, single-cell droplet making, droplet incubation, and real-time readout for leukocyte secretion profiling of neutrophil elastase, granzyme B, and metalloproteinase. We calibrated the device, optimized the protocols, and tested the leukocyte secretion of acute heart failure (AHF) patients at admission and predischarge. This paper highlights the presence of single-cell enzymatic immune phenotypes independent of CD marker labeling, which could potentially elucidate the innate immune response states. We found that patients recovering from AHF showed a corresponding reduction in immune-cell enzymatic secretion levels and donor-specific enzymatic signatures were observed, which suggests patient-to-patient heterogeneous immune response. This platform presents opportunities to elucidate the complexities of the immune response from a single drop of blood and bridge the current technological, biological, and medical gap in understanding immune response and biological triggers.

A practical biphasic contrast media injection protocol strongly enhances the aorta and pulmonary artery simultaneously using a single CT angiography scan.

BACKGROUND: Enhancement profiles of the pulmonary artery (PA) and aorta differ when using computed tomography (CT) angiography. Our aim was to determine the optimal CT protocol for a one-time CT scan that assesses both blood vessels. METHODS: We prospectively enrolled 101 cases of CT angiography in patients with suspected pulmonary embolism or aortic dissection from our center between 2018 and 2020. We also retrospectively collected the data of 40 patients who underwent traditional two-time CT scans between 2015 and 2018. Patients were divided into four groups: test bolus (TB) I, TB II, bolus-tracking (BT) I, and BT II. The enhancement of the PA and aorta, and the radiation doses used in the four groups were collected. Those who underwent two-time scans were classified into the traditional PA or aorta scan groups. Data were compared between the BT and traditional groups. RESULTS: The aortic enhancement was highest in BT II (294.78 ± 64.48 HU) followed BT I (285.18 ± 64.99 HU), TB II (186.58 ± 57.53 HU), and TB I (173.62 ± 69.70 HU). The radiation dose used was lowest in BT I (11.85 ± 5.55 mSv) and BT II (9.07 ± 3.44 mSv) compared with that used in the traditional groups (20.07 ± 7.78 mSv) and accounted for half of the traditional group (45.17-59.02%). The aortic enhancement was also highest in BT II (294.78 ± 64.48 HU) followed by BT I (285.18 ± 64.99 HU) when compared with that in the traditional aorta scan group (234.95 ± 94.18 HU). CONCLUSION: Our CT protocol with a BT technique allows for a lower radiation dose and better image quality of the PA and aorta than those obtained using traditional CT scans. TRIAL REGISTRATION: NCT04832633, retrospectively registered in April 2021 to the clinical trial registry.

Identification of Specific Endobronchial Ultrasound Features to Differentiate Sarcoidosis From Other Causes of Lymphadenopathy.

OBJECTIVES: We hypothesized that specific endobronchial ultrasound (EBUS) features may differentiate sarcoidosis from other causes of lymphadenopathy. METHODS: We conducted this retrospective observational study from January 2014 to January 2019 to analyze patients with intrathoracic lymphadenopathy who underwent EBUS-guided transbronchial needle aspiration. Ultrasound features, including nodal size, margin, echogenicity, the presence or absence of calcification, a central hilar structure, the coagulation necrosis sign, nodal conglomeration, and the septal vessel sign in the color Doppler mode were recorded and compared between 3 groups. RESULTS: Of the 90 included patients, 15 had a diagnosis of tuberculosis; 56 had a diagnosis of sarcoidosis; and 19 had a diagnosis of malignant lymph nodes by EBUS-guided transbronchial needle aspiration. The presence of nodal conglomeration (94.6% versus 60.0% versus 5.3%; P < .001), the septal vessel sign in the color Doppler mode (55.4% versus 13.3% versus 15.8%; P = .002), and a distinct margin (73.2% versus 13.3% versus 47.4%; P < .001) were significantly higher in the sarcoidosis group than in the tuberculosis lymphadenopathy and malignant lymph node groups. The presence of the coagulation necrosis sign (8.9% versus 93.3% versus 31.6%; P < .001) was significantly lower in the sarcoidosis group than in tuberculosis lymphadenopathy and malignant lymph node groups. A multivariate analysis showed that the presence of nodal conglomeration, the absence of coagulation necrosis, and the presence of the septal vessel sign in the color Doppler mode were independent predictive factors for the diagnosis of sarcoidosis. CONCLUSIONS: The presence of nodal conglomeration, the absence of coagulation necrosis, and the presence of the septal vessel sign in the color Doppler mode in lymph nodes on EBUS are predictive of sarcoidosis.