Prediction of disease progression in individuals with subjective cognitive decline using brain network analysis.

OBJECTIVE: The objective of this study is to explore potential differences in brain functional networks at baseline between individuals with progressive subjective cognitive decline (P-SCD) and stable subjective cognitive decline (S-SCD), as well as to identify potential indicators that can effectively distinguish between P-SCD and S-SCD. METHODS: Alzheimer's Disease Neuroimaging Initiative (ADNI) database was utilized to enroll SCD individuals with a follow-up period of over 3 years. This study included 39 individuals with S-SCD, 15 individuals with P-SCD, and 45 cognitively normal (CN) individuals. Brain functional networks were constructed based on the AAL template, and graph theory analysis was performed to determine the topological properties. RESULTS: For global metric, the S-SCD group exhibited stronger small-worldness with reduced connectivity among nearby nodes and accelerated compensatory information transfer capacity. For nodal efficiency, the S-SCD group showed increased connectivity in bilateral posterior cingulate gyri (PCG). However, for nodal local efficiency, the P-SCD group exhibited significantly reduced connectivity in the right cerebellar Crus I compared with the S-SCD group. CONCLUSION: There are differences in brain functional networks at baseline between P-SCD and S-SCD groups. Furthermore, the right cerebellar Crus I region may be a potentially useful brain area to distinguish between P-SCD and S-SCD.

White matter substrates underlying morphological awareness deficit in Chinese children with developmental dyslexia.

BACKGROUND: Morphological awareness (MA) deficit is strongly associated with Chinese developmental dyslexia (DD). However, little is known about the white matter substrates underlying the MA deficit in Chinese children with DD. METHODS: In the current study, 34 Chinese children with DD and 42 typical developmental (TD) children were recruited to complete a diffusion magnetic resonance imaging scan and cognitive tests for MA. We conducted linear regression to test the correlation between MA and DTI metrics, the structural abnormalities of the tracts related to MA, and the interaction effect of DTI metrics by group on MA. RESULTS: First, MA was significant related to the right inferior occipito-frontal fascicle (IFO) and inferior longitudinal fsciculus (ILF), the bilateral thalamo-occipital (T_OCC) and the left arcuate fasciculus (AF); second, compared to TD children, Chinese children with DD had lower axial diffusivity (AD) in the right IFO and T_OCC; third, there were significant interactions between metrics (fractional anisotropy (FA) and radial diffusivity (RD)) of the right IFO and MA in groups. The FA and RD of the right IFO were significantly associated with MA in children with DD but not in TD children. CONCLUSION: In conclusion, compared to TD children, Chinese children with DD had axonal degeneration not only in the ventral tract (the right IFO) but also the visuospatial tract (the right T_OCC) which were associated with their MA deficit. And Chinese MA involved not only the ventral tracts, but also the visuospatial pathway and dorsal tracts.

A systematic review of the impacts of remote patient monitoring (RPM) interventions on safety, adherence, quality-of-life and cost-related outcomes.

Due to rapid technological advancements, remote patient monitoring (RPM) technology has gained traction in recent years. While the effects of specific RPM interventions are known, few published reviews examine RPM in the context of care transitions from an inpatient hospital setting to a home environment. In this systematic review, we addressed this gap by examining the impacts of RPM interventions on patient safety, adherence, clinical and quality of life outcomes and cost-related outcomes during care transition from inpatient care to a home setting. We searched five academic databases (PubMed, CINAHL, PsycINFO, Embase and SCOPUS), screened 2606 articles, and included 29 studies from 16 countries. These studies examined seven types of RPM interventions (communication tools, computer-based systems, smartphone applications, web portals, augmented clinical devices with monitoring capabilities, wearables and standard clinical tools for intermittent monitoring). RPM interventions demonstrated positive outcomes in patient safety and adherence. RPM interventions also improved patients' mobility and functional statuses, but the impact on other clinical and quality-of-life measures, such as physical and mental health symptoms, remains inconclusive. In terms of cost-related outcomes, there was a clear downward trend in the risks of hospital admission/readmission, length of stay, number of outpatient visits and non-hospitalisation costs. Future research should explore whether incorporating intervention components with a strong human element alongside the deployment of technology enhances the effectiveness of RPM. The review highlights the need for more economic evaluations and implementation studies that shed light on the facilitators and barriers to adopting RPM interventions in different care settings.

Brain abscess caused by Streptococcus anginosus group: Three case reports.

BACKGROUND: This case series investigated the clinical manifestations, diagnoses, and treatment of cerebral abscesses caused by Streptococcus anginosus. We retrospectively analyzed the clinical characteristics and outcomes of three cases of cerebral abscesses caused by Streptococcus anginosus and conducted a comprehensive review of relevant literature. CASE SUMMARY: Case 1 presented with a history of left otitis media and exhibited high fever, confusion, and vomiting as primary symptoms. Postoperative pus culture indicated a brain abscess caused by Streptococcus constellatus infection. Case 2 experienced dizziness for two days as the primary symptom. Postoperative pus culture suggested an intermediate streptococcal brain abscess. Case 3: Enhanced head magnetic resonance imaging (MRI) and diffusion-weighted imaging revealed occupancy of the left temporal lobe, initially suspected to be a metastatic tumor. However, a postoperative pus culture confirmed the presence of a brain abscess caused by Streptococcus anginosus infection. The three cases presented in this case series were all patients with community-acquired brain abscesses resulting from angina caused by Streptococcus group infection. All three patients demonstrated sensitivity to penicillin, ceftriaxone, vancomycin, linezolid, chloramphenicol, and levofloxacin. Successful treatment was achieved through stereotaxic puncture, drainage, and ceftriaxone administration with a six -week course of antibiotics. CONCLUSION: Preoperative enhanced head MRI plays a critical role in distinguishing brain tumors from abscesses. Selecting the correct early diagnostic methods for brain abscesses and providing timely intervention are very important. This case series was in accordance with the CARE guidelines.

Impaired effective functional connectivity in the social preference of children with autism spectrum disorder.

Background: The medial prefrontal cortex (mPFC), amygdala (Amyg), and nucleus accumbens (NAc) have been identified as critical players in the social preference of individuals with ASD. However, the specific pathophysiological mechanisms underlying this role requires further clarification. In the current study, we applied Granger Causality Analysis (GCA) to investigate the neural connectivity of these three brain regions of interest (ROIs) in patients with ASD, aiming to elucidate their associations with clinical features of the disorder. Methods: Resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from the ABIDE II database, which included 37 patients with ASD and 50 typically developing (TD) controls. The mPFC, Amyg, and NAc were defined as ROIs, and the differences in fractional amplitude of low-frequency fluctuations (fALFF) within the ROIs between the ASD and TD groups were computed. Subsequently, we employed GCA to investigate the bidirectional effective connectivity between the ROIs and the rest of the brain. Finally, we explored whether this effective connectivity was associated with the social responsiveness scale (SRS) scores of children with ASD. Results: The fALFF values in the ROIs were reduced in children with ASD when compared to the TD group. In terms of the efferent connectivity from the ROIs to the whole brain, the ASD group exhibited increased connectivity in the right cingulate gyrus and decreased connectivity in the right superior temporal gyrus. Regarding the afferent connectivity from the whole brain to the ROIs, the ASD group displayed increased connectivity in the right globus pallidus and decreased connectivity in the right cerebellar Crus 1 area and left cingulate gyrus. Additionally, we demonstrated a positive correlation between effective connectivity derived from GCA and SRS scores. Conclusion: Impairments in social preference ASD children is linked to impaired effective connectivity in brain regions associated with social cognition, emotional responses, social rewards, and social decision-making. This finding further reveals the potential neuropathological mechanisms underlying ASD.

Safety, efficacy, and survival outcomes of immune checkpoint inhibitors rechallenge in patients with cancer: a systematic review and meta-analysis.

BACKGROUNDS: There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due to immune-related adverse events (irAEs) or progressive disease (PD). Here, we performed a meta-analysis to elucidate the possible benefits of ICI rechallenge in patients with cancer. METHODS: Systematic searches were conducted using PubMed, Embase, and Cochrane Library databases. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of irAEs were the outcomes of interest. RESULTS: Thirty-six studies involving 2026 patients were analyzed. ICI rechallenge was associated with a lower incidence of all-grade (OR, 0.05; 95%CI, 0.02-0.13, P < .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, P < .05) when compared with initial ICI treatment. Though no significant difference was observed between rechallenge and initial treatment regarding ORR (OR, 0.69; 95%CI, 0.39-1.20, P = .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, P = 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, P < .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, P < .05) than those who discontinued ICI therapy permanently. Subgroup analysis revealed that for patients who stopped initial ICI treatment because of irAEs, rechallenge showed similar safety and efficacy with initial treatment, while for patients who discontinued ICI treatment due to PD, rechallenge caused a significant increase in the incidence of high-grade irAEs (OR, 4.97; 95%CI, 1.98-12.5, P < .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, P < .05). CONCLUSION: ICI rechallenge is generally an active and feasible strategy that is associated with relative safety, similar efficacy, and improved survival outcomes. Rechallenge should be considered individually with circumspection, and randomized controlled trials are required to confirm these findings.

Altered effective connectivity on rapid automatized naming deficits in Chinese children with developmental dyslexia: An rs-fMRI study with Ganger causality analysis.

Rapid Automatized Naming (RAN) is the core defect of developmental dyslexia (DD), requiring collaboration among brain areas to complete. However, it's still unclear which effective connectivity (EC) among brain areas are crucial for RAN deficits in Chinses children with DD. The current study aims to explore the EC among brain areas related to RAN deficits in Chinese children with DD. We recruited 36 Chinese children with DD and 64 typically developing (TD) children aged 8-12 to complete resting-state functional magnetic resonance imaging (rs-fMRI) scan. Granger causality analysis (GCA) was employed to analysis the EC among brain areas related to RAN, and to calculate the relationship between EC and RAN scores. Compared to TD group, the DD group exhibited significantly decreased EC from left precentral gyrus (PG) to right precuneus, left anterior cingulate and paracingulate gyrus (ACG), left calcarine and right angular, from left middle frontal gyrus (MFG) to left calcarine. Additionally, the DD group showed increased EC from right cuneus to left inferior frontal gyrus triangular part (IFGtri). The EC from left PG to left ACG was positively correlated with letters-RAN score. The results showed Chinese children with DD had both defect and compensatory mechanisms for their RAN deficits. The decreased EC output from left PG may be the core problem of the RAN deficits, which may influence the integration of visual-spatial information, attention, memory retrieval, and speech motor in speech production. The current study has important clinic implications for establishing intervention measures targeted brain.

The effect of age, sex, and eastern cooperative oncology group performance status on the efficacy and safety of immune checkpoint inhibitors in patients with hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: The effect of age, sex, and eastern cooperative oncology group performance status (ECOG PS) on the efficacy and safety of immune checkpoint inhibitor (ICI) therapy among hepatocellular carcinoma (HCC) patients remains elusive. Thus, a meta-analysis was conducted to evaluate whether such effects exist. RESEARCH DESIGN AND METHODS: Eligible studies in PubMed, Embase, and Cochrane Library databases were retrieved. RESULTS: One-hundred-and-eleven studies involving 14,768 HCC patients were included. The findings indicated that the ECOG PS didn't have a significant effect on the ORR and PFS in ICI-treated HCC patients (higher ECOG PS vs. lower ECOG PS: ORR: OR = 0.78, 95%CI = 0.55-1.10; PFS: HR = 1.15, 95%CI = 0.97-1.35), while those patients with a higher ECOG PS may have a worse OS (HR = 1.52, 95% CI = 1.26-1.84). There is no significant evidence of the effect of age (older vs. younger) or sex (males vs. females) on the efficacy of ICI therapy in HCC. CONCLUSION: ICI therapy in HCC should not be restricted strictly to certain patients in age or sex categories, while HCC patients with higher ECOG PS may require closer medication or follow-up strategy during ICI therapy. PROSPERO REGISTRATION: CRD42024518407.

Efficacy and effect on lipid profiles of Ainuovirine-based regimen versus Efavirenz-based regimen in treatment-naïve people with HIV-1 at week 24: A real-world, retrospective, multi-center cohort study.

This study aimed to compare the efficacy and effect on lipid profiles of Ainuovirine (ANV)- and efavirenz (EFV) -based regimens in treatment-naïve people living with HIV-1 (PLWH) at week 24. The proportion of PLWH achieving HIV-1 RNA < the limit of quantification in the ANV group was significantly higher than that in the EFV group (89.18% vs. 76.04%, P = 0.002). The mean change of log10 HIV-1 RNA from baseline was greater (-4.34 vs. -4.18, P < 0.001), the median change from baseline in CD4+ T cell count increased more (106.00 cells/µL vs. 92.00 cells/µL, P = 0.007) in the ANV group, while the CD4+/CD8+ ratio was similar (0.15 vs. 0.20, P = 0.167) between the two groups. The mean changes from baseline in total cholesterol (-0.02 for ANV vs. 0.25 mmol/L for EFV, P < 0.001), triglyceride (-0.14 for ANV vs. 0.11 mmol/L for EFV, P = 0.024), and low-density lipoprotein cholesterol (-0.07 for ANV vs. 0.15 mmol/L for EFV, P < 0.001) was significantly different between the two groups. The percentage of patients with improved lipid profiles was significantly higher in the ANV group (37.44 %) than in the EFV group (29.55%, P = 0.0495). The incidence of any adverse events in the ANV group was significantly lower than that in the EFV group at week 12 (6.2% vs. 30.7%, P < 0.001) and was comparable at week 24 (3.6% vs. 5.5%, P = 0.28). The ANV-based regimen was well tolerated and lipid-friendly in treatment-naïve PLWH.

Role of hepatitis B core-related antigen in predicting the occurrence and recurrence of hepatocellular carcinoma in patients with chronic hepatitis B: A systemic review and meta-analysis.

BACKGROUND AND AIM: The purpose of the current study was to investigate the predictive value of hepatitis B core-related antigen (HBcrAg) on the occurrence and recurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). METHODS: We searched PubMed, Embase, Scopus, and Web of Science from database inception to April 6, 2023. Pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was calculated for the occurrence and recurrence of HCC. RESULTS: Of the 464 articles considered, 18 articles recruiting 10 320 patients were included. The pooled results showed that high serum HBcrAg level was an independent risk factor for the occurrence of HCC in CHB patients (adjusted HR = 3.12, 95% CI: 2.40-4.06, P < 0.001, I2 = 43.2%, P = 0.043; OR = 5.65, 95% CI: 3.44-5.82, P < 0.001, I2 = 0.00%, P = 0.42). Further subgroup analysis demonstrated that the predictive ability of HBcrAg for the occurrence of HCC is not influenced by the hepatitis B e antigen (HBeAg) status or the use of nucleoside/nucleotide analogs (NAs). In addition, our meta-analysis also suggests that HBcrAg is a predictor of HCC recurrence (adjusted HR = 1.71, 95% CI: 1.26-2.32, P < 0.001, I2 = 7.89%, P = 0.031). CONCLUSIONS: For patients with CHB, serum HBcrAg may be a potential predictive factor for the occurrence of HCC, regardless of HBeAg status or NA treatment. It may also serve as a novel prognostic biomarker for the recurrence of HCC. More studies are needed to confirm our conclusions.

Combined aerobic and strength exercise training on biological ageing in Singaporean breast cancer patients: protocol for the Breast Cancer Exercise Intervention (BREXINT) Pilot Study.

Breast cancer (BC) is the most prominent cancer amongst women, but fortunately, early diagnosis and advances in multimodality treatments have improved patient survivability. Cancer survivors, however, experience increased biological ageing which may accelerate other co-morbidities. Exercise intervention is a promising clinical adjuvant approach to improve BC patients' physiological function, recovery from treatment, and quality of life. However, the effects of combined aerobic and strength exercise training on biological ageing in BC patients have not been studied. The Breast Cancer Exercise Intervention (BREXINT) Pilot Study will evaluate the effects of a 24-week combined aerobic and strength exercise intervention against usual care in 50 BC patients' post-treatment randomised to either group. The primary outcomes include changes in cardiorespiratory fitness, muscle strength, cancer-related symptoms, and rate of biological ageing following exercise intervention period. The secondary outcomes include habitual physical activity measured with tri-axial accelerometery and supporting questionnaires, including physical activity, food diary, and quality of life questionnaires. This study will identify the effects of combined aerobic exercise strength training on biological ageing in BC patients from Singapore. Results from this study could further support the implementation of regular exercise programmes as routine care for cancer patients.

A Serum Pharmacochemistry and Network Pharmacology-based Approach to Study the Anti-depressant Effect of Chaihu-Shugan San.

AIMS: The aim of this study is to explore the anti-depressant mechanism of Chaihu- Shugan San based on serum medicinal chemistry and network pharmacology methods. BACKGROUND: Depression lacks effective treatments, with current anti-depressants ineffective in 40% of patients. Chaihu-Shugan San (CHSGS) is a well-known traditional Chinese medicine compound to treat depression. However, the chemical components and the underlying mechanisms targeting the liver and brain in the anti-depressant effects of CHSGS need to be elucidated. METHODS: The chemical components of CHSGS in most current network pharmacology studies are screened from TCMSP and TCMID databases. In this study, we investigated the mechanism and material basis of soothing the liver and relieving depression in the treatment of depression by CHSGS based on serum pharmacochemistry. The anti-depressant mechanism of CHSGS was further verified by proteomics and high-throughput data. RESULTS: Through serum medicinal chemistry, we obtained 9 bioactive substances of CHSGS. These ingredients have good human oral bioavailability and are non-toxic. Based on liver ChIPseq data, CHSGS acts on 8 targets specifically localized in the liver, such as FGA, FGB, and FGG. The main contributors to CHSGS soothing the liver qi targets are hesperetin, nobiletin, ferulic acid, naringin and albiflorin. In addition, network pharmacology analysis identified 9 blood components of CHSGS that corresponded to 63 anti-depressant targets in the brain. Among them, nobiletin has the largest number of anti-depressant targets, followed by glycyrrhizic acid, ferulic acid, albiflorin and hesperetin. We also validated the anti-depressant mechanism of CHSGS based on hippocampal proteomics. CHSGS exerts anti-depressant effects on synaptic structure and neuronal function by targeting multiple synapse related proteins. CONCLUSION: This study not only provides a theoretical basis for further expanding the clinical application of CHSGS, but also provides a series of potential lead compounds for the development of depression drugs.

Numb cheek syndrome in breast cancer: a case report.

Background: Numb cheek syndrome, a rare corollary of numb chin syndrome, is due to infra-orbital neuropathy. It can occur in association with an underlying malignancy, which can cause neuropathy by direct malignant nerve infiltration or via a paraneoplastic mechanism. Although numb cheek syndrome has been reported in association with a variety of cancers, it has previously not been reported in association with breast cancer. We report a case of left breast cancer presenting with left numb cheek syndrome. Case presentation: A 65-year-old woman presented to the Neurology clinic with a 7-month history of left cheek numbness and occasional cheek tenderness. Examination revealed slightly diminished pin-prick sensation in the left cheek and a vaguely palpable left breast lump. A magnetic resonance imaging scan of the brain showed abnormal enhancement of the left maxillary nerve at the foramen rotundum, but cerebrospinal fluid analysis was normal. Mammography, ultrasound scans, and core biopsy of the left breast confirmed the diagnosis of invasive left breast carcinoma (estrogen and progesterone receptor negative, c-erb-B2 equivocal, fluorescence in-situ hybridization negative). There was no evidence of distant metastases on computed tomography and bone scintigraphy scans. The patient underwent neoadjuvant chemotherapy (4 cycles of doxorubicin and cyclophosphamide, followed by 4 cycles of paclitaxel and carboplatin), and left breast wide excision and sentinel lymph node biopsy, and a repeat magnetic resonance imaging scan performed 2 months after surgical resection showed resolution of the left maxillary nerve enhancement. The patient's left numb cheek symptoms improved over a course of 5 months after cancer resection but did not completely resolve. Conclusions: Our case represents the first reported left numb cheek syndrome in association with breast cancer, due to maxillary neuropathy without any discrete mass or compressive cause. To avoid delays in diagnosing malignancy, physicians and surgeons should be aware that numb cheek syndrome can occur in association with an underlying malignancy, and that breast cancer should be counted amongst the possibilities.

Patellar tilt, congruence angle, and tibial tubercle-trochlear groove distance are correlated with positive J-sign in adolescents.

PURPOSE: The J-sign is a clinical evaluation tool that assesses for patellar maltracking and is considered positive if lateral translation of the patella in extension, in the pattern of an inverted J is observed. This study aims to determine the association of clinical J-sign with imaging features noted on dynamic kinematic computed tomography (DKCT). METHODS: A retrospective review was conducted by reviewing the clinical records of all patients aged 18 years or younger who had a CT patellar tracking scan done between 1 January 2005 to 31 December 2016 in a single institution. Patients who had the presence or absence of a 'J-sign' evaluated clinically were included. Radiographic parameters evaluated using the axial cuts include the patellar tilt angle, congruence angle, Dejour's classification, femoral sulcus angle, trochlear groove depth, and Wiberg's classification. Patients were then divided into two groups based on the presence or absence of J-sign on clinical examination. The radiographic measurements were then analyzed for association with the presence or absence of J-sign on clinical examination. RESULTS: Patients with a positive J-sign had an increased patellar tilt of 23.3° ± 14.2° and an increased congruence angle of 47.1° ± 28.5° when measured in extension as compared to a patellar tilt of 18.3° ± 10.8° and a congruence angle of 32.1° ± 20.8° in patients with a negative J-sign (p = 0.024 and 0.004, respectively). Comparisons of the change in congruence angles with the knee in full extension and at 20° flexion also yielded significantly higher change of 28.0° ± 20.4° in patients with a positive J-sign as compared to 11.9° ± 17.5° in patients with a negative J-sign. Patients with a positive J-sign also had an increased TT-TG distance of 17.6 ± 5.6 mm as compared to a TT-TG distance of 14.7 ± 6.9 mm in patients with a negative J-sign (p = 0.01). CONCLUSION: Patients with a positive J-sign had an increased patellar tilt and an increased congruence angle when measured in extension. Increased TT-TG distance was also significantly associated with positive J-sign. Patients with a positive J-sign also had a greater change in their congruence angle when measured with the knee in full extension and at 20° of flexion.

Combination of tibial tubercle transfer, medial patellofemoral ligament reconstruction, trochleoplasty and lateral release for patellofemoral instability provides good middle- to long-term outcomes in adolescents.

PURPOSE: There are limited studies that have reported the middle- to long-term outcomes of combined procedures consisting of more than two procedures for patellofemoral instability. The current study aims to investigate and report the middle- to long-term outcomes of a combination procedure of tibial tubercle transfer, medial patellofemoral ligament reconstruction, trochleoplasty and lateral release for patellofemoral instability in patients aged 18 years and below. METHODS: In the cohort study, all patients aged 18 years old or younger who underwent a combination procedure of tibial tubercle transfer, medial patellofemoral ligament reconstruction, trochleoplasty and lateral release for recurrent patellofemoral instability were included. RESULTS: A total of 21 patients were included in the study. All patients had no further patellofemoral dislocation, pain and apprehension following the 4-in-1 surgery (p < 0.01). There was a significant improvement in the Kujala score from 36.1 (SD 12.9) pre-operatively to 93.1 (SD 3.6) post-operatively (p < 0.001). The patients also had a statistically significant improvement in their radiological factors, including the patellar tilt angle (p < 0.001), sulcus angle (p = 0.001), trochlear groove depth (p = 0.041), tibial tubercle-trochlear groove distance (p < 0.001) and Caton-Deschamps index (p = 0.001). CONCLUSION: A combination procedure of tibial tubercle transfer, medial patellofemoral ligament reconstruction, trochleoplasty and lateral release leads to good middle- to long-term subjective, functional and radiographic outcomes for patients with recurrent patellofemoral instability and underlying predisposing factors of increased TT-TG distance of more than 20 mm, Dejour B or D trochlear dysplasia and medial patellofemoral ligament rupture. LEVEL OF EVIDENCE: IV.

Transcriptome data-based status of PI3K/AKT/mTOR pathway indicates heterogeneity and immune modulation in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited treatment options. The PI3K/AKT/mTOR pathway is commonly activated in PDAC and plays a critical role in its progression. METHODS AND RESULTS: In this study, the effect of taselisib (a selective PI3K inhibitor) on PDAC cell proliferation was investigated, and a significant decrease in viability was observed with increasing concentrations of taselisib. Differential analysis on samples from the Genotype-Tissue Expression and The Cancer Genome Atlas databases revealed 24 dysregulated PI3K/AKT/mTOR pathway-related genes (PRGs). Unsupervised clustering-based analysis of transcriptome cohorts revealed two clusters with high consistency between RNA-seq and microarray cohorts. Cluster B had higher enrichment of immune cells, particularly CD8+ T cells, and lower levels of immunosuppressive Treg cells. Moreover, we investigated the relationship between drug sensitivity and different clusters and found that cluster A had a better response to PI3K/AKT/mTOR pathway-related inhibitors and chemotherapy. Finally, cluster A exhibited significant activation of PI3K/AKT/mTOR and related oncogenic pathways, contributing to poor prognosis. The study also developed a risk score based on the expression profiles of PRGs and machine learning, which showed a significant increase in overall survival time among patients in the low-risk group. Importantly, the PI3K/AKT/mTOR pathway could be used to better predict individual risk scores, as evidenced by stratified survival analysis. CONCLUSIONS: These findings suggest that targeting the PI3K/AKT/mTOR pathway may have therapeutic potential in PDAC, and distinct pathway states, immune modulation and tumor microenvironments have prognostic value.

Transcriptomic landscape of endothelial cells: Key tumor microenvironment components indicating variable clinical outcomes in pancreatic ductal adenocarcinoma.

Endothelial cells (ECs) present in the tumor microenvironment (TME) exhibit significant diversity that may impact the efficacy of anti-tumor treatments. Thus, our study sought to elucidate the various clusters of ECs present in pancreatic ductal adenocarcinoma (PDAC) and explore their possible interactions and influence on clinical outcomes. We obtained single-cell transcriptome data from 24 PDAC tumors and 11 normal pancreases, minimizing any batch effects between samples. Next, we compared the relative abundance of various ECs clusters across distinct sample types. Pseudo-time analysis was employed to investigate the differentiation origin of ECs. A variety of bioinformatics methods were used to investigate potential communication between ECs and malignant cells, as well as assess metabolic changes, pathway alterations, and immune-related markers expression within distinct EC clusters. Lastly, we investigated the impact of particular ECs clusters on patient prognosis in bulk transcriptome data. Our study identified seven distinct clusters of ECs, denoted as CA4+ ECs, MMP2+ ECs, SPP1+ ECs, MT1F+ ECs, CCL5+ ECs, RGS5+ ECs, and TYROBP+ ECs. Pseudo-time analysis suggested that the loss of CA4+ ECs and MT1F+ ECs may promote malignant progression. Cell communication elucidated that MT1F+ ECs exhibited the strongest outgoing interaction strength, whereas RGS5+ ECs displayed the strongest incoming interaction strength. Furthermore, TYROBP+ ECs exhibited greater metabolic activity, and notably, CCL5+ ECs displayed increased expression of immune-related molecules. Lastly, across cohorts of bulk transcriptome levels, CA4+ ECs, MT1F+ ECs, and RGS5+ ECs consistently demonstrated prognostic indicative effects. PDAC patients exhibit the presence of seven distinct EC clusters, each demonstrating significant metabolic and immunological heterogeneity. Targeted therapeutic approaches directed toward CA4+ ECs and MT1F+ ECs may prove advantageous in addressing challenges associated with PDAC treatment. Additionally, variations in the relative abundance of CA4+ ECs, MT1F+ ECs, and RGS5+ ECs were indicated as predictive of patient prognosis.