Age at menarche and idiopathic pulmonary fibrosis: a two-sample mendelian randomization study.

BACKGROUND: Sex difference in the incidence rate of idiopathic pulmonary fibrosis (IPF) indicates that estrogen has a certain protective effect on the disease. Nevertheless, there is a dearth of study investigating the association between factors pertaining to endogenous estrogen exposure level, such as age at menarche (AAM) in women, and IPF. Our study intended to employ Mendelian randomization (MR) method to elucidate the causal association between AAM and IPF. METHODS: Our study utilized AAM as a measure of endogenous estrogen exposure and investigated its causal effect on the risk of IPF through MR. We employed the inverse variance weighted (IVW) method to assess the causal relationship between AAM and IPF risk, with supplementary analyses conducted using the weighted median estimator (WME) and MR-Egger method. Several sensitivity analyses were performed to assess the dependability of MR estimates. RESULTS: A total of 9 selected single nucleotide polymorphisms (SNPs) significantly associated with AAM were selected as instrumental variables. The IVW method showed that genetically later AAM was associated with an increased risk of IPF (odds ratio [OR] = 1.0014, 95%confidence interval [CI] = 1.0005-1.0023, p = 0.001). The median weighting method and the MR-Egger method obtained similar estimates, and no heterogeneity or pleiotropy was found, indicating that the results were robust. CONCLUSIONS: Our MR study suggested a causal relationship between a later onset of menarche and a heightened susceptibility to IPF.

Value of rapid on-site evaluation combined with interventional pulmonology techniques in the diagnosis of pulmonary cryptococcosis.

OBJECTIVES: The aim of this study is to evaluate the diagnostic value of rapid on-site evaluation (ROSE) combined with computed tomography-guided percutaneous needle biopsy (CT-PNB) or radial endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB) for pulmonary cryptococcosis (PC). METHODS: Clinical data of 33 patients diagnosed with PC at the Third Affiliated Hospital of Soochow University between February 2018 and June 2023 were retrospectively analysed. Patients were divided into the CT-PNB and EBUS-TBLB groups based on the intervention method, and the diagnostic positivity rate and incidence of complications were compared between the two groups. RESULTS: Compared with the final diagnosis, the positive diagnostic rates of ROSE, histopathology and serum CrAg of all patients were 81.8% (27/33), 72.7% (24/33) and 63.6% (21/33), respectively. The average turnaround times of the three methods were 0.1 (0.1-0.2) h, 96.0 (48.0-120.0) h and 7.8 (4.5-13.6) h, respectively (P < 0.001). The coincidence rate between histopathology and ROSE was 84.8% with a kappa value of 0.574. The positive diagnostic rate for PC was significantly higher in the CT-PNB group than in the EBUS-TBLB group (92.9% vs. 57.9%), and the difference was statistically significant (P < 0.05). Combined with the ROSE results, the positive diagnostic rate in the EBUS-TBLB group increased to 84.2% (16/19). CONCLUSION: ROSE has commendable accuracy and timeliness, and CT-PNB offers further advantages in this regard. ROSE enhances the diagnostic efficiency of EBUS-TBLB for PC and is safe and effective.

Design and evaluation of α-helix-based peptide inhibitors for blocking PD-1/PD-L1 interaction.

The current research in tumor immunotherapy indicates that blocking the protein-protein interaction (PPI) between PD-1 and its ligand, PD-L1, may be one of the most effective treatments for cancer patients. The α-helix is a common elements of protein secondary structure and is often involved in protein interaction. Thus, α-helix-based peptides could mimic proteins involved in such interactions and are also capable of modulating PPI in vivo. In this study, starting from a potential α-helix-rich protein, we designed a series of α-helix-based peptide candidates to block PD-1/PD-L1 interaction. These candidates were first screened using molecular docking and molecular dynamics simulations, and then their capacities to inhibit PD-1/PD-L1 interactions and to restore antitumor immune activities were investigated using the HTRF assay, SPR assay, cellular co-culture experiments and animal model experiments. Two peptides exhibited the best anti-tumor effects and the strong ability to restore the immunity of tumor-infiltrating T-cells. Further D-amino acid substitution was employed to improve the serum stability of peptide candidate, making the intravenous administration easier while maintaining the therapeutic efficacy. The resultant peptides showed promise as checkpoint inhibitors for application in tumor immunotherapy. These findings suggested that our strategy for developing peptides starting from an α-helical structure could be used in the design of bioactive inhibitors to potential block protein-protein interactions.

The management and outcome of cryptococcosis in patients with different immune statuses and treatment protocols: A multicenter real-world study in Jiangsu Province - China.

OBJECTIVE: The incidence of cryptococcosis is increasing in non-immunocompromised patients. However, the evidence on proper management is inadequate in this population. We conducted this multi-center real-world study in pulmonary cryptococcosis patients with different immune statuses, so as to provide practical evidence for optimized clinical management of cryptococcosis, especially for mild-to-moderate immunodeficient diseases patients. METHODS: This is a prospective observational study. The clinical data of patients with proven cryptococcosis were collected and analyzed from 7 tertiary teaching hospitals in Jiangsu Province, China from January, 2013 to December, 2018. Proven cases include pulmonary cryptococcosis, cryptococcal meningitis, cryptococcemia and cutaneous cryptococcosis. Patients were followed up over 24 months. According to their immune status, patients with cryptococcosis were divided into three groups, namely immunocompetent group (IC), mild-to-moderate immunodeficient diseases group (MID), severe immunodeficient diseases group (SID). Meanwhile, pulmonary crypotococcosis (PC) and extrapulmonary crypotococcosis (EPC) were also classified and analyzed. RESULTS: 255 proven cases of cryptococcosis were enrolled. Finally, 220 cases completed the follow-up. 143 proven cases (65.0%) were immunocompetent (IC), 41 cases (18.6%) were MID, and 36 cases (16.4%) were SID. 174 cases (79.1%) were PC and 46 cases (20.9%) were EPC. The mortality was significantly higher in SID and MID patients [47.2% (SID) vs. 12.2% (MID) vs. 0.0% (IC), p<0.001]. The mortality was also significantly higher in EPC patients [45.7% vs. 0.6% (PC), p<0.001]. Patients with alternative initial antifungal treatment had higher mortality than patients with guideline recommended initial treatment [23.1% vs. 9.5%, p=0.041]. In MID group, the mortality of receiving alternative initial antifungal treatment was significantly higher than recommended initial treatment [2/3 vs. 3/34(8.8%), p=0.043]. In pulmonary cryptococcosis patients with MID, the mortality was very similar to IC group [0.0% vs. 0.0% (IC)], lower than SID group [0.0% vs. 11.1% (SID), p=0.555]. However, in extrapulmonary cryptococcosis patients with MID, the mortality was significantly higher than that in IC [62.5% vs. 0.0% (IC)], and similar to SID patients [62.5% vs. 59.3% (SID)]. CONCLUSION: The immune status exert a significant influence on the management and prognosis of cryptococcosis patients. The mortality of cryptococcosis patients with MID is higher than that of immunocompetent patients. For MID patients with pure pulmonary cryptococcosis, it is acceptable to take the treatment recommended as IC patients. For the MID patients with extrapulmonary cryptococcosis, the mortality is high and the initial treatment should follow the regimen for SID patients. Following the recommended treatment regimen in the IDSA guideline can reduce mortality in patients with cryptococcosis. Starting on alternative initial antifungal treatment may bring worse outcomes.

The clinical value of Aspergillus-specific IgG antibody test in the diagnosis of nonneutropenic invasive pulmonary aspergillosis.

OBJECTIVES: Aspergillus-specific IgG antibody (Asp IgG) has been successfully applied in the diagnosis of chronic pulmonary aspergillosis. We explored its value in nonneutropenic invasive pulmonary aspergillosis (IPA) by a multicenter, prospective, and controlled study. METHODS: We enrolled 372 clinically suspected nonneutropenic patients with IPA from February 2015 to August 2022. After excluding 4 cases with Aspergillus colonization, the remaining 368 cases were finally confirmed as patients with IPA (n = 99), or non-IPA patients (n = 269) consisting of community-acquired pneumonia (n = 206), tuberculosis (n = 22), nontuberculous mycobacteria (n = 5), lung abscess (n = 6), or noninfectious diseases (n = 30). Asp IgG in plasma samples was tested by enzyme-linked immunosorbent assay. RESULTS: At cut-off value of ≥80 AU/mL, Asp IgG had much higher sensitivity (59.6% vs. 19.2%, p < 0.0001), but lower specificity (77.0% vs. 96.3%, p < 0.0001) than serum galactomannan (GM) (cut-off value of ≥1.0), and similar sensitivity (59.6% vs. 55.6%, p = 0.611) but lower specificity (77.0% vs. 91.2%, p = 0.001) than bronchoalveolar lavage fluid (BALF) GM (cut-off value of ≥1.0), respectively. Combination diagnosis of either positive for Asp IgG or BALF GM had higher sensitivity (81.0% vs. 55.6%, p = 0.002), but lower specificity (75.2% vs. 91.2%, p = 0.001) than BALF GM alone. The receiver operating characteristic curve showed that Asp IgG had an optimal diagnostic value when the cut-off value was 56.6 AU/ml, and the sensitivity and specificity were 77.8% and 63.9%, respectively. DISCUSSIONS: The diagnostic value of Asp IgG for IPA is superior to serum GM, and a little inferior to BALF GM in nonneutropenic patients with IPA. Considering the convenience of taking blood samples, it is a good screening and diagnostic method for nonneutropenic patients with IPA, especially for those who cannot bear invasive procedures.

Clinical Features, Treatment, and Outcome of Psittacosis Pneumonia: A Multicenter Study.

Background: We aimed to describe psittacosis pneumonia and risk factors for developing severe pneumonia in this multicenter clinical study. Methods: We collected the data of psittacosis pneumonia cases diagnosed with metagenomic next-generation sequencing (mNGS) assay from April 2018 to April 2022 in 15 tertiary hospitals in China. Results: A total of 122 patients were enrolled; 50.0% had a definite history of bird exposure. In 81.2% of cases, onset happened in autumn or winter. The common symptoms were fever (99.2%), cough (63.1%), fatigue (52.5%), shortness of breath (50.0%), chills (37.7%), central nervous system symptoms (36.9%), myalgia (29.5%), and gastrointestinal tract symptoms (15.6%). Laboratory tests showed that >70% of cases had elevated C-reactive protein, procalcitonin, erythrocyte sedimentation rate, D-dimer, lactate dehydrogenase, and aspartate aminotransferase, and >50% had hyponatremia and hypoproteinemia. The most common imaging finding was consolidation (71.3%), and 42.6% of cases met the criteria for severe pneumonia. Age >65 years and male sex were the risk factors for severe pneumonia. The effective proportion of patients treated with tetracyclines was higher than that of fluoroquinolones (66/69 [95.7%] vs 18/58 [31.0%]; P < .001), and the median defervescence time was shorter. After medication adjustment when the diagnosis was clarified, 119 of 122 (97.5%) patients were finally cured and the other 3 (2.5%) died. Conclusions: Psittacosis pneumonia has a high rate of severe disease. Proven diagnosis could be rapidly confirmed by mNGS. Tetracycline therapy had a rapid effect and a high cure rate.

Diagnosis values of Dectin-1 and IL-17 levels in plasma for invasive pulmonary aspergillosis in bronchiectasis.

Background: Among immunocompetent patients, patients with bronchiectasis are considered to be a high-risk group for invasive pulmonary aspergillosis (IPA). Early diagnosis and treatment can improve the prognosis of patients. Objectives: We aimed to investigate the diagnostic value of Dectin-1 and IL-17 for diagnosing IPA with bronchiectasis. Methods: We retrospectively collected data on patients with bronchiectasis who had been hospitalized in the Third Affiliated Hospital of Soochow University between September 2018 to December 2021. Dectin-1, IL-17 and GM were measured by enzyme-linked immunosorbent assays. Results: A total of 129 patients were analyzed in the study, of whom 33 had proven or probable IPA with bronchiectasis. The remaining 96 patients served as controls. The plasma Dectin-1 and IL-17 levels in the IPA group were significantly higher than that in the control group (P=0.005; P<0.001). The plasma GM, BALF GM, plasma Dectin-1 and IL-17 assays had sensitivities of 39.4%, 62.5%, 69.7% and 78.8%, respectively, and specificities of 89.2%, 91.5%, 72.9% and 71.9%, respectively. The sensitivity of Dectin-1 and IL-17 in plasma was higher than that in plasma and BALF GM. while the specificity is lower than that of plasma and BALF GM. The diagnostic sensitivity and specificity of plasma GM combined with IL-17 for IPA in bronchiectasis were greater than 80%. The combination of plasma GM and IL-17 can improve the sensitivity of the GM test, but does not reduce the diagnostic specificity. The plasma Dectin-1 and IL-17 showed positive linear correlations with the bronchiectasis severity Index (BSI) score in linear regression. Conclusions: Plasma Dectin-1 and IL-17 levels were significantly higher in bronchiectasis patients with IPA. The sensitivity of Dectin-1 and IL-17 was superior to that of GM for the diagnosis of IPA in patients with bronchiectasis. The combination of GM and IL-17 in plasma is helpful for the diagnosis of IPA in bronchiectasis patients who cannot tolerate invasive procedures.

Prediction model for synergistic anti-tumor multi-compound combinations from traditional Chinese medicine based on extreme gradient boosting, targets and gene expression data.

Traditional Chinese medicine (TCM) is characterized by synergistic therapeutic effect involving multiple compounds and targets, which provide potential new therapy for the treatment of complex cancer conditions. However, the main contributors and the underlying mechanisms of synergistic TCM cancer therapies remain largely undetermined. Machine learning now provides a new approach to determine synergistic compound combinations from complex components of TCM. In this study, a prediction model based on extreme gradient boosting (XGBoost) algorithm was constructed by integrating gene expression data of different cancer cell lines, targets information of natural compounds and drug response data. Radix Paeoniae Rubra (RPR) was selected as a model herbal sample to evaluate the reliability of the constructed model. The optimal XGBoost prediction model achieved a good performance with Mean Square Error (MSE) of 0.66, Mean Absolute Error (MAE) of 0.61, and the Root Mean Squared Error (RMSE) of 0.81 on test dataset. The superior synergistic anti-tumor combinations of D15 (Paeonol[Formula: see text][Formula: see text][Formula: see text]Ethyl gallate) and D13 (Paeoniflorin[Formula: see text][Formula: see text][Formula: see text]Paeonol) were successfully predicted from RPR and experimentally validated on MCF-7 cells. Moreover, the combination of D13 could work as a main contributor to a synergistic anti-proliferative activity in the compatibility of RPR and Cortex Moutan (CM). Our XGBoost model could be a reliable tool for the efficient prediction of synergistic anti-tumor multi-compound combinations from TCM.

In Silico Screening and Validation of PDGFRA Inhibitors Enhancing Radioiodine Sensitivity in Thyroid Cancer.

Aberrant activation of platelet-derived growth factor receptor α (PDGFRA) has been implicated in tumorigenesis and radioiodine resistance of thyroid cancer, indicating its therapeutic potential. In the present study, we confirmed the association between PDGFRA and radioiodine resistance in thyroid cancer using bioinformatics analysis and constructed a prediction model of PDGFRA inhibitors using machine learning and molecular docking approaches. We then performed a virtual screening of a traditional Chinese medicine (TCM) derived compound library and successfully identified 4',5,7-trimethoxyflavone as a potential PDGFRA inhibitor. Further characterization revealed a significant inhibitory effect of 4',5,7-trimethoxyflavone on PDGFRA-MAPK pathway activation, and that it could upregulate expression of sodium iodide symporter (NIS) as well as improve radioiodine uptake capacity of radioiodine-refractory thyroid cancer (RAIR-TC), suggesting it a potential drug lead for the development of new RAIR-TC therapy.

Identification of Potential RBPJ-Specific Inhibitors for Blocking Notch Signaling in Breast Cancer Using a Drug Repurposing Strategy.

Notch signaling is a key parameter in regulating cell fate during tissue homeostasis, and an aberrant Notch pathway can result in mammary gland carcinoma and has been associated with poor breast cancer diagnosis. Although inhibiting Notch signaling would be advantageous in the treatment of breast cancer, the currently available Notch inhibitors have a variety of side effects and their clinical trials have been discontinued. Thus, in search of a more effective and safer Notch inhibitor, inhibiting recombinant signal binding protein for immunoglobin kappaJ region (RBPJ) specifically makes sense, as RBPJ forms a transcriptional complex that activates Notch signaling. From our established database of more than 10,527 compounds, a drug repurposing strategy-combined docking study and molecular dynamic simulation were used to identify novel RBPJ-specific inhibitors. The compounds with the best performance were examined using an in vitro cellular assay and an in vivo anticancer investigation. Finally, an FDA-approved antibiotic, fidaxomicin, was identified as a potential RBPJ inhibitor, and its ability to block RBPJ-dependent transcription and thereby inhibit breast cancer growth was experimentally verified. Our study demonstrated that fidaxomicin suppressed Notch signaling and may be repurposed for the treatment of breast cancer.

A novel SRSF3 inhibitor, SFI003, exerts anticancer activity against colorectal cancer by modulating the SRSF3/DHCR24/ROS axis.

As the modulation of serine/arginine-rich splicing factor 3 (SRSF3) may be therapeutically beneficial to colorectal cancer (CRC) treatment, the identification of novel SRSF3 inhibitors is highly anticipated. However, pharmaceutical agents targeting SRSF3 have not yet been discovered. Here, we propose a functional SRSF3 inhibitor for CRC therapy and elucidate its antitumor mechanisms. We found high expression of SRSF3 in 70.6% CRC tissues. Silencing SRSF3 markedly inhibits the proliferation and migration of CRC cells through suppression of its target gene 24-dehydrocholesterol reductase (DHCR24). This is evidenced by the links between SRSF3 and DHCR24 in CRC tissues. The novel SRSF3 inhibitor SFI003 exhibits potent antitumor efficacy in vitro and in vivo, which drives apoptosis of CRC cells via the SRSF3/DHCR24/reactive oxygen species (ROS) axis. Moreover, SFI003 is druggable with suitable pharmacokinetic properties, bioavailability, and tumor distribution. Thus, SRSF3 is a novel potential therapeutic target for CRC. Its inhibitor SFI003 may be developed as an anticancer therapeutic.

A Strategy for the Effective Optimization of Pharmaceutical Formulations Based on Parameter-Optimized Support Vector Machine Model.

Engineering pharmaceutical formulations is governed by a number of variables, and the finding of the optimal preparation is intricately linked to the exploration of a multiparametric space through a variety of optimization tasks. As a result, making such optimization activities simpler is a significant undertaking. For the purposes of this study, we suggested a prediction model that was based on least square support vector machine (LSSVM) and whose parameters were optimized using the particle swarm optimization algorithm (PSO-LSSVM model). Other in silico optimization methods were used and compared, including the LSSVM and the back propagation (BP) neural networks algorithm. PSO-LSSVM demonstrated the highest performance on the test dataset, with the lowest mean square error. In addition, two dosage forms, quercetin solid dispersion and apigenin nanoparticles, were selected as model formulations due to the wide range of formulation compositions and manufacturing factors used in their production. Three different models were used to predict the ideal formulations of two different dosage forms, and in real world, the Taguchi orthogonal design arrays were used to optimize the formulations of each dosage form. It is clear that the predicted performance of two formulations using PSO-LSSVM was both consistent with the outcomes of the Taguchi orthogonal planned experiment, demonstrating the model's good reliability and high usefulness. Together, our PSO-LSSVM prediction model has the potential to accurately predict the best possible formulations, reduce the reliance on experimental effort, accelerate the process of formulation design, and provide a low-cost solution to drug preparation optimization.

Deep learning-based multi-drug synergy prediction model for individually tailored anti-cancer therapies.

While synergistic drug combinations are more effective at fighting tumors with complex pathophysiology, preference compensating mechanisms, and drug resistance, the identification of novel synergistic drug combinations, especially complex higher-order combinations, remains challenging due to the size of combination space. Even though certain computational methods have been used to identify synergistic drug combinations in lieu of traditional in vitro and in vivo screening tests, the majority of previously published work has focused on predicting synergistic drug pairs for specific types of cancer and paid little attention to the sophisticated high-order combinations. The main objective of this study is to develop a deep learning-based approach that integrated multi-omics data to predict novel synergistic multi-drug combinations (DeepMDS) in a given cell line. To develop this approach, we firstly created a dataset comprising of gene expression profiles of cancer cell lines, target information of anti-cancer drugs, and drug response against a large variety of cancer cell lines. Based on the principle of a fully connected feed forward Deep Neural Network, the proposed model was constructed using this dataset, which achieved a high performance with a Mean Square Error (MSE) of 2.50 and a Root Mean Squared Error (RMSE) of 1.58 in the regression task, and gave the best classification accuracy of 0.94, an area under the Receiver Operating Characteristic curve (AUC) of 0.97, a sensitivity of 0.95, and a specificity of 0.93. Furthermore, we utilized three breast cancer cell subtypes (MCF-7, MDA-MD-468 and MDA-MB-231) and one lung cancer cell line A549 to validate the predicted results of our model, showing that the predicted top-ranked multi-drug combinations had superior anti-cancer effects to other combinations, particularly those that were widely used in clinical treatment. Our model has the potential to increase the practicality of expanding the drug combinational space and to leverage its capacity to prioritize the most effective multi-drug combinational therapy for precision oncology applications.

The role of pentraxin3 in plasma and bronchoalveolar lavage fluid in COPD patients with invasive pulmonary aspergillosis.

BACKGROUND: The use of galactomannan (GM) testing in plasma and bronchoalveolar lavage fluid (BALF) has improved the diagnosis of invasive pulmonary aspergillosis (IPA) in patients with chronic obstructive pulmonary disease (COPD); however, the high false-positive rate leads to overdiagnosis. Pentraxin 3 (PTX3) as an indicator of inflammation plays an important role in resistance to Aspergillus infections. This study aimed to investigate the diagnostic value of PTX3 for diagnosing IPA with COPD. METHODS: We retrospectively collected data on patients with suspected COPD and IPA who had been hospitalized in the Third Affiliated Hospital of Soochow University between September 2017 and November 2020. PTX3 and GM were measured using enzyme-linked immunosorbent assays. RESULTS: A total of 165 patients were included in the study, of whom 35 had confirmed or probable IPA. The remaining 130 patients served as controls. The median plasma and BALF PTX3 levels were significantly higher in patients with IPA than in control patients (3.74 ng/mL vs. 1.29 ng/mL, P < 0.001; and 3.88 ng/mL vs. 1.58 ng/mL, P < 0.001 in plasma and BALF, respectively). The plasma GM, plasma PTX3, BALF GM, and BALF PTX3 assays had sensitivities of 60.0%, 77.1%, 78.6%, and 89.3%, respectively, and specificities of 73.8%, 69.2%, 80.7%, and 77.1%, respectively. The sensitivity of PTX3 in plasma and BALF was higher than that of GM. However, the specificity of PTX3 and GM did not differ significantly between the IPA group and the control group. The specificity of the assays for the diagnosis of IPA was > 90% in patients who were PTX3-positive and GM-positive in plasma and BALF. CONCLUSIONS: BALF and plasma PTX3 levels were significantly higher in COPD patients with IPA. The sensitivity of PTX3 was superior to that of GM for diagnosing IPA in patients with COPD. The combination of GM and PTX3 is useful for the diagnosis of IPA in patients with COPD.

Clinical features of cryptococcosis in patients with different immune statuses: a multicenter study in Jiangsu Province-China.

BACKGROUND: Current guidelines support different management of cryptococcosis between severely immunodeficient and immunocompetent populations. However, few studies have focused on cryptococcosis patients with mild-to-moderate immunodeficiency. We performed this study to determine the clinical features of pulmonary (PC) and extrapulmonary cryptococcosis (EPC) and compared them among populations with different immune statuses to support appropriate clinical management of this public health threat. METHODS: All cases were reported by 14 tertiary teaching hospitals in Jiangsu Province, China from January 2013 to December 2018. The trends in incidence, demographic data, medical history, clinical symptoms, laboratory test indicators, imaging characteristics and diagnostic method of these patients were then stratified by immune status, namely immunocompetent (IC, patients with no recognized underlying disease or those with an underlying disease that does not influence immunity, such as hypertension), mild-to-moderate immunodeficiency (MID, patients with diabetes mellitus, end-stage liver or kidney disease, autoimmune diseases treated with low-dose glucocorticoid therapy, and cancer treated with chemotherapy) and severe immunodeficiency (SID, patients with acquired immunodeficiency syndrome, haematologic malignancies, solid organ transplantation or haematologic stem cell transplantation, idiopathic CD4 lymphocytosis, agranulocytosis, aggressive glucocorticoid or immunosuppressive therapy and other conditions or treatments that result in severe immunosuppression). RESULTS: The clinical data of 255 cryptococcosis patients were collected. In total, 66.3% of patients (169) were IC, 16.9% (43) had MID, and 16.9% (43) had SID. 10.1% of the patients (17) with IC were EPC, 18.6% of the patients (8) with MID were EPC, and 74.4% of patients (32) were EPC (IC/MID vs. SID, p < 0.001). Fever was more common in the SID group than in the IC and MID groups (69.8% vs. 14.8% vs. 37.2%, p < 0.001). Of chest CT scan, most lesions were distributed under the pleura (72.7%), presenting as nodules/lumps (90.3%) or consolidations (10.7%). Pleural effusion was more common in SID group compared to IC group (33.3% vs. 2.4%, p < 0.001). Positivity rate on the serum capsular polysaccharide antigen detection (CrAg) test was higher in the SID group than in the other two groups [100.0% vs. 84.4% (MID) vs. 78.2% (IC), p = 0.013]. Positivity rate on the serum CrAg test was also higher in cryptococcal meningitis patients than in PC patients (100.0% vs. 79.5%, p = 0.015). CONCLUSIONS: The clinical presentation of MID patients is intermediate between SID and IC patients and is similar to that of IC patients. The serum CrAg test is more sensitive for the identification of SID or EPC patients.

STK3-ALK, a Novel ALK Rearrangement in Non-Small Cell Lung Cancer With Sensitivity to Tyrosine Kinase Inhibitors: A Case Report.

Anaplastic lymphoma kinase (ALK) rearrangement occurs in 5% to 8% of patients with non-small cell lung cancer (NSCLC). More than 90 different ALK fusion partners have been discovered in NSCLC patients, and ALK tyrosine kinase inhibitors (TKIs) such as crizotinib and alectinib have achieved tumor responses in patients with advanced ALK-positive NSCLC. Here, we report the case of a patient with an advanced NSCLC carrying a novel serine/threonine kinase 3 (STK3)-ALK rearrangement, which was identified by targeted next-generation sequencing (NGS) and was confirmed by RNA sequencing. Anti-ALK immunohistochemistry (IHC) staining also revealed the high expression of ALK. The patient benefitted from alectinib treatment after experiencing crizotinib resistance and achieved an overall response to TKI of over 14 months. At the timepoint of submission of this manuscript, this patient is still receiving alectinib treatment with a good tolerance. This study provides meaningful insights into the potential treatment option for NSCLC patients with brain metastases harboring STK3-ALK fusions and highlights the advantages of NGS in rapidly identifying novel molecular targets.

Therapeutic effects of pentoxifylline on invasive pulmonary aspergillosis in immunosuppressed mice.

BACKGROUND: The most common and severe infection of Aspergillus fumigatus is invasive pulmonary aspergillosis (IPA), which is usually seen in immunocompromised patients. Neutropenia is the primary risk factor implicated in IPA; however, IPA also occurs in patients without neutropenia, namely, those who are immunosuppressed owing to long-term corticosteroid use. With IPA-associated mortality as high as 51-79%, novel and effective treatment strategies are urgently needed. Pentoxifylline (PTX) has been shown to competitively inhibit the family 18 chitinases in fungi, which may be an new antifungal therapy. Hence, the aim of our study was to compare neutropenic and non-neutropenic IPA mouse models, and to evaluate the effect of PTX on IPA in immunosuppressed mice. METHODS: C57BL/6J mice were pre-treated with cyclophosphamide and hydrocortisone. Neutropenic model IPA mice (CTX-IPA) and non-neutropenic IPA mice (HC-IPA) were established by intranasal administration of Aspergillus fumigatus spore suspension. A subset of each group was injected with PTX post-infection. Among these groups, we compared overall survival, pulmonary fungal burden, lung hispathology, and myeloperoxidase (MPO), interleukin 8 (IL-8), and mammalian chitinase concentration in the bronchoalveolar lavage fluid (BALF). RESULTS: The survival rate of the HC-IPA group was higher than that of the CTX-IPA group, and pulmonary fungal burden was also lower (p < 0.05). The CTX-IPA group showed infiltration of alveolae and blood vessels by numerous hyphae of A. fumigatus. The HC-IPA group exhibited destruction of bronchi, expansion of alveolar septa, increased macrophages aggregation, significant neutrophil infiltration and a few hyphae in peribronchial areas. After PTX treatment, improvement was observed in survival duration and pulmonary fungal burden in HC-IPA mice. MPO and IL-8 levels were lower in the HC-IPA + PTX group compared to the corresponding levels in the HC-IP group. Chitotriosidase (CHIT1) and Chitinase 3-like 1 (CHI3L1) expression in the HC-IPA group was decreased after PTX treatment (p < 0.05). CONCLUSION: PTX was found to exert a therapeutic effect in a non-neutropenic mouse model of IPA, which may lead to the development of novel strategies for IPA treatment.

Development of simultaneous interaction prediction approach (SiPA) for the expansion of interaction network of traditional Chinese medicine.

BACKGROUND: Due to the lack of enough interaction data among compositions, targets and diseases, it is difficult to construct a complete network of Traditional Chinese Medicine (TCM) that comprehensively reflects active compositions and their synergistic network in terms of specific diseases. Therefore, mapping of the full spectrum of interaction between compounds and their targets is of central importance when we use network pharmacology approach to explore the therapeutic potential of the TCM. METHODS: To address this challenge, we developed a large-scale simultaneous interaction prediction approach (SiPA) integrated one interaction network based simple inference model (SIM), focusing on 'logical relevance' between compounds, proteins or diseases, and another compound-target correlation space based interaction prediction model (CTCS-IPM) that was built on the basis of the canonical correlation analysis (CCA) to estimate the position of compounds (or targets) in compound-protein correlated space. Then SiPA was applied to discover reliable multiple interactions for interaction network expansion of a TCM, compound Salvia miltiorrhiza. By means of network analysis, potential active compounds and their related network synergy underlying cardiovascular diseases were evaluated between expanded and original interaction networks. Part of new interactions were validated with existing experimental evidence and molecular docking. RESULTS: As evaluated with known test dataset, the established combination approach was proved to make highly accurate prediction, showing a well prediction performance for the SIM and a high recall rate of 85.2% for the CTCS-IPM. Then 710 pairs of new compound-target interactions, 24 pairs of new compound-cardiovascular disease interactions and 294 pairs of new cardiovascular disease-protein interactions were predicted for compound Salvia miltiorrhiza. Results of network analysis suggested the network expansion could dramatically improve the completeness and effectiveness of the network. Validation results of literature and molecular docking manifested that inferred interactions had good reliability. CONCLUSIONS: We provided a practical and efficient way for large-scale inference of multiple interactions of TCM ingredients, which was not limited by the lack of negative samples, sample size and target 3D structures. SiPA could help researchers more accurately prioritize the effective compounds and more completely explore network synergy of TCM for treating specific diseases, indicating a potential way for effectively identifying candidate compound (or target) in drug discovery.

Layered MoS2 nanosheets modified by biomimetic phospholipids: Enhanced stability and its synergistic treatment of cancer with chemo-photothermal therapy.

Cancer is a huge challenge humanity facing today, and single chemical treatments inevitably have shortcomings such as poor selectivity and large side effects. This paper constructed an egg yolk phospholipids modified molybdenum disulfide (MoS2) nanocarrier system for the treatment of tumors via the combination of chemotherapy and photothermal therapy. The lipid-modified layered MoS2 (MoS2-Lipid) nanocomposite was synthesized by simple physical adsorption. The lipid modification strongly enhanced the stability of MoS2 nanosheets and the nanocarrier has a large drug loading amount with pH dependent DOX release profile, an excellent photothermal property, and an ideal cellular uptake property. Therefore, we combined chemotherapy and photothermal therapy to treat tumors synergistically. Through in vitro cell experiments, pure nanocomposite had no obvious cytotoxicity to cells, and the synergistic treatment of tumors by chemotherapy and photothermal therapy was more effective than any single treatment. More importantly, in vivo experiments indicated that lipid modification enhanced the accumulation of the nanocarrier in mice tumors, thus a better photothermal performance could be seen compared with original MoS2 nanosheets. In summary, the MoS2-lipid nanocomposite is a promising nanocarrier for the treatment of tumors by chemo and photothermal therapy.