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Asian Pacific Journal of Cancer... Jun 2024There have been several reports on rechallenge with docetaxel, cabazitaxel, abiraterone acetate, or ethinylestradiol for metastatic castration-resistant prostate cancer...
OBJECTIVE
There have been several reports on rechallenge with docetaxel, cabazitaxel, abiraterone acetate, or ethinylestradiol for metastatic castration-resistant prostate cancer (mCRPC). However, the efficacy of enzalutamide rechallenge for mCRPC has not been evaluated.
METHODS
We retrospectively reviewed 63 consecutive patients who received enzalutamide for mCRPC at our institution between 2014 and 2022. Eight of these patients underwent rechallenge with enzalutamide after disease progression on prior enzalutamide and other therapy and were the focus of this study. The prostate-specific antigen (PSA) response (PSA decrease >50%), PSA progression-free survival, treatment duration, overall survival (OS) after CRPC, and treatment-related adverse events were evaluated.
RESULTS
PSA decline to enzalutamide rechallenge was observed in 6 patients (75%), of which 2 patients had a PSA response. The median treatment duration was 4 months (range 1-12) and median PSA progression-free survival was 3 months (range 1-7). Median OS after CRPC was 41 months. OS after CRPC was not increased in patients with a PSA response. No toxicities were worse than grade ≥3.
CONCLUSION
Enzalutamide rechallenge achieved a PSA response in a quarter of our patients with mCRPC after disease progression on prior enzalutamide. However, no improvement of OS was identified in these patients.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Phenylthiohydantoin; Nitriles; Benzamides; Retrospective Studies; Aged; Middle Aged; Prostate-Specific Antigen; Follow-Up Studies; Survival Rate; Prognosis; Aged, 80 and over; Antineoplastic Agents
PubMed: 38918645
DOI: 10.31557/APJCP.2024.25.6.1863 -
PloS One 2024Neutrophil proteinase 3 (PR3) is an important drug target for inflammatory lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis. Drug...
Neutrophil proteinase 3 (PR3) is an important drug target for inflammatory lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis. Drug discovery efforts targeting PR3 require active enzyme for in vitro characterization, such as inhibitor screening, enzymatic assays, and structural studies. Recombinant expression of active PR3 overcomes the need for enzyme supplies from human blood and in addition allows studies on the influence of mutations on enzyme activity and ligand binding. Here, we report the expression of recombinant PR3 (rPR3) using a baculovirus expression system. The purification and activation process described resulted in highly pure and active PR3. The activity of rPR3 in the presence of commercially available inhibitors was compared with human PR3 by using a fluorescence-based enzymatic assay. Purified rPR3 had comparable activity to the native human enzyme, thus being a suitable alternative for enzymatic studies in vitro. Further, we established a surface plasmon resonance-based assay to determine binding affinities and kinetics of PR3 ligands. These methods provide valuable tools for early drug discovery aiming towards treatment of lung inflammation.
Topics: Humans; Myeloblastin; Ligands; Recombinant Proteins; Animals; Sf9 Cells; Surface Plasmon Resonance; Protein Binding; Baculoviridae; Kinetics; Gene Expression; Spodoptera
PubMed: 38917138
DOI: 10.1371/journal.pone.0294827 -
JAMA Network Open Jun 2024Prostate cancer is a prevalent disease among men worldwide, exhibiting substantial heterogeneity in presentation and outcomes influenced by various factors, including... (Observational Study)
Observational Study
IMPORTANCE
Prostate cancer is a prevalent disease among men worldwide, exhibiting substantial heterogeneity in presentation and outcomes influenced by various factors, including race and ethnicity. Disparities in incidence, stage at diagnosis, and survival rates have been observed between Black men and those of other races and ethnicities.
OBJECTIVE
To compare prostate cancer outcomes between Black men and men with other race (Asian, Hispanic, Indigenous, Middle Eastern, White, Multiracial, and Other) in a universal health care system, with race and ethnicity self-reported.
DESIGN, SETTING, AND PARTICIPANTS
This was a prospective, observational cohort study of men diagnosed with prostate cancer between June 1, 2014, and August 28, 2023, who self-identified race and ethnicity. Participants included men who had been prospectively enrolled in the Alberta Prostate Cancer Research Initiative from the 2 major urology referral centers in Alberta (University of Alberta and University of Calgary). All men with prostate cancer enrolled in the initiative were included.
EXPOSURE
Race and ethnicity.
MAIN OUTCOMES AND MEASURES
The primary outcome was the stage and grade of prostate cancer at diagnosis. Further outcomes included age and prostate-specific antigen level at diagnosis, initial treatment modality, time from diagnosis to initial treatment, and prostate cancer-specific, metastasis-free, and overall survivals.
RESULTS
A total of 6534 men were included; 177 (2.7%) were Black, and 6357 (97.3%) had another race or ethnicity. Men who identified as Black were diagnosed with prostate cancer at an earlier age (mean [SD], 62.0 [8.2] compared with 64.6 [7.7] years; P < .001) and had a lower Charlson Comorbidity Index rating (14% compared with 7% ≤ 1; P < .001) compared with men of other races. Men who identified as Black had similar prostate-specific antigen levels at diagnosis, TNM category (74% vs 74% with T1-T2; P = .83) and Gleason Grade Group (34% compared with 35% Gleason Grade Group 1; P = .63). Black men had similar rates of prostate cancer-specific (hazard ratio [HR], 1.10; 95% CI, 0.41-2.97; P = .85), metastasis-free (HR, 0.88; 95% CI, 0.42-1.46; P = .44), and overall (HR, 0.55; 95% CI, 0.25-1.24; P = .15) survival.
CONCLUSIONS AND RELEVANCE
The findings of this cohort study suggest that Black men, despite being diagnosed at a younger age, experience comparable prostate cancer outcomes compared with men of other races.
Topics: Male; Humans; Prostatic Neoplasms; Aged; Middle Aged; Prospective Studies; Alberta; Canada; Black or African American; Neoplasm Grading; Black People; Neoplasm Staging; Prostate-Specific Antigen
PubMed: 38916889
DOI: 10.1001/jamanetworkopen.2024.18475 -
Scientific Reports Jun 2024Identification of an early biomarker and effective testing device to differentiate dry eye disease secondary to autoimmune disease (Sjögren's syndrome dry eye disease)...
Identification of an early biomarker and effective testing device to differentiate dry eye disease secondary to autoimmune disease (Sjögren's syndrome dry eye disease) from non-Sjögren's dry eye disease are prerequisites for appropriate treatment. We aimed to demonstrate the capacity of a new photo-detection device to evaluate tear lactoferrin levels as a tool for differentiating systemic conditions associated with dry eye disease. Patients with non-Sjögren's and Sjögren's syndrome dry eye disease (n = 54 and n = 52, respectively) and controls (n = 11) were enrolled. All participants completed the Ocular Surface Disease Index questionnaire. Tear collection was performed with Schirmer test, and tear break-up time was examined using a slit lamp. Tear lactoferrin was evaluated using our newly developed photo-detection device. The average lactoferrin concentration was significantly lower in samples from patients with non-Sjögren's dry eye disease (0.337 ± 0.227 mg/mL, n = 54) and Sjögren's syndrome dry eye disease (0.087 ± 0.010 mg/mL, n = 52) than in control samples (1.272 ± 0.54 mg/mL, n = 11) (p < 0.0001). Further, lactoferrin levels were lower in patients with Sjögren's syndrome dry eye disease than in those with non-Sjögren's dry eye disease (p < 0.001). Our cost-effective, antibody-free, highly sensitive photo-detection device for evaluating tear lactoferrin levels can assist ophthalmologists in differentiating different types of dry eye diseases.
Topics: Lactoferrin; Humans; Tears; Sjogren's Syndrome; Female; Middle Aged; Dry Eye Syndromes; Male; Adult; Biomarkers; Diagnosis, Differential; Aged; Fluorescence
PubMed: 38914667
DOI: 10.1038/s41598-024-65487-2 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Jun 2024Human lactoferrin (HLF), an essential nutrient found in breast milk, possesses antibacterial, anti-inflammatory, and immune-enhancing properties. In this study, the...
Human lactoferrin (HLF), an essential nutrient found in breast milk, possesses antibacterial, anti-inflammatory, and immune-enhancing properties. In this study, the effects of three constitutive promoters (P, P, and P) and three inducible promoters (P, P, and P) on the expression of HLF were compared using G601 as the host strain. The results showed that the highest expression of HLF, reaching 651.57 μg/L, was achieved when regulated by the P promoter. Furthermore, the combinational optimization of ribosome binding site (RBS) and signal peptides was investigated, and the optimal combination of RBS6 and SP resulted in increased HLF expression to 1 099.87 μg/L, with 498.68 μg/L being secreted extracellularly. To further enhance HLF secretion, the metal cations-related gene was knocked out, leading to an extracellular HLF level of 637.28 μg/L. This study successfully demonstrated the secretory expression of HLF in . through the selection and optimization of expression elements, laying the foundation for the development of efficient . cell factories for lactoprotein synthesis.
Topics: Bacillus subtilis; Lactoferrin; Humans; Promoter Regions, Genetic; Recombinant Proteins
PubMed: 38914499
DOI: 10.13345/j.cjb.230785 -
The Canadian Journal of Urology Jun 2024Prostate cancer is the second most common cancer in men across the world. Prior to PSA testing, men usually presented with locally advanced disease detected on digital...
Prostate cancer is the second most common cancer in men across the world. Prior to PSA testing, men usually presented with locally advanced disease detected on digital rectal exam or with metastatic disease. PSA ushered in the era of serum biomarkers for prostate cancer. It has taken over three decades to refine the role of PSA in prostate cancer detection. The lack of specificity has spurred research into finding better, readily obtainable biomarkers with high sensitivity and specificity. The trick is to find the prostate cancers that are a threat, not the ones that aren't. Over the last decade and more, many biomarkers have been proposed and tested (HK-2, Pro-PSA, PCA3, TMPRSS2:ERG fusion transcripts, miRNA, just to name a few) but we still await that magical combination of a readily available, reproducible, and hopefully inexpensive biomarker with high sensitivity and specificity. The authors describe the use of a peptide labeled fluorophore for the VPAC1 receptors that are expressed on malignant prostate cancer cells shed in the urine. After initial feasibility work, the authors collected urine from 318 men with lower urinary tract symptoms and a PSA > 4. The patients underwent prostate biopsy yielding Grade Group 2 or higher prostate cancer in 158 patients. One hundred fifty-four or those patients with cancer had a positive result for the biomarker. The sensitivity of the test was 100%, the specificity was 97.56%, positive predictive value was 97.47%, and negative predictive value was 100%.1 These are impressive numbers for a urine biomarker (or any biomarker). This work is certainly promising, BUT, we have seen promising early data on many biomarkers. In this study, the mean PSA in the cancer group was 34.53 ng/mL versus 9.41 in the control (negative) group. Since patients with infection were excluded, the significantly different PSA levels seemed to be selecting the cancers as well. Time and follow up will determine if the "negative biopsy" controls were truly negative. Can the technique and these results be reproduced? The true test will be how this biomarker consistently performs across a broader population of men with a lower, more homogenous PSA elevation. I will eagerly await results of continued study of this promising biomarker for prostate cancer.
Topics: Humans; Male; Prostatic Neoplasms; Biomarkers, Tumor; Sensitivity and Specificity; Prostate-Specific Antigen; Aged; Middle Aged
PubMed: 38912943
DOI: No ID Found -
Frontiers in Immunology 2024Complement activation is considered to contribute to the pathogenesis of severe SARS-CoV-2 infection, mainly by generating potent immune effector mechanisms including a...
Complement activation is considered to contribute to the pathogenesis of severe SARS-CoV-2 infection, mainly by generating potent immune effector mechanisms including a strong inflammatory response. Involvement of the lectin complement pathway, a major actor of the innate immune anti-viral defense, has been reported previously. It is initiated by recognition of the viral surface Spike glycoprotein by mannose-binding lectin (MBL), which induces activation of the MBL-associated protease MASP-2 and triggers the proteolytic complement cascade. A role for the viral nucleoprotein (N) has also been reported, through binding to MASP-2, leading to protease overactivation and potentiation of the lectin pathway. In the present study, we reinvestigated the interactions of the SARS-CoV-2 N protein, produced either in bacteria or secreted by mammalian cells, with full-length MASP-2 or its catalytic domain, in either active or proenzyme form. We could not confirm the interaction of the N protein with the catalytic domain of MASP-2 but observed N protein binding to proenzyme MASP-2. We did not find a role of the N protein in MBL-mediated activation of the lectin pathway. Finally, we showed that incubation of the N protein with MASP-2 results in proteolysis of the viral protein, an observation that requires further investigation to understand a potential functional significance in infected patients.
Topics: Mannose-Binding Protein-Associated Serine Proteases; Humans; SARS-CoV-2; Complement Pathway, Mannose-Binding Lectin; COVID-19; Protein Binding; Coronavirus Nucleocapsid Proteins; Complement Activation; Mannose-Binding Lectin; Phosphoproteins
PubMed: 38911852
DOI: 10.3389/fimmu.2024.1419165 -
Medical Ultrasonography Jun 2024
Topics: Humans; Aneurysm, False; Thrombin; Embolization, Therapeutic; Ultrasonography, Interventional; Hemostatics; Male; Combined Modality Therapy; Treatment Outcome; Female
PubMed: 38909366
DOI: 10.11152/mu-4397 -
BMC Medical Research Methodology Jun 2024Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline differences, and (2) the relationship of baseline differences with effects on low-density lipoprotein-cholesterol (LDL-c) and clinical outcomes in the trials.
METHODS
We performed a meta-epidemiological study. PubMed, Embase, regulatory reports, ClinicalTrials.gov and company websites were searched for trials. Seven baseline characteristics (mean age, LDL-c, BMI, percentage males, diabetics, smokers, and hypertensives) and five outcomes (LDL-c, major adverse cardiac events, serious adverse events, any adverse events, all-cause mortality) were extracted. We calculated (1) range and distribution of baseline imbalances (sign-test), (2) pooled baseline differences and heterogeneity (meta-analysis), (3) differences in SDs around continuous variables (sign-test and pooling), and (4) the relationship of baseline differences with outcomes (meta-regression). The comparisons of PCSK9-inhibitor groups with either placebo or ezetimibe were analysed separately and combined.
RESULTS
We identified 43 trials with 63,193 participants. Baseline characteristics were frequently missing. Many trials showed small baseline imbalances, but some large imbalances. Only baseline BMI showed a statistically significant lower pooled mean for the drug versus placebo groups (MD -0.16; 95% CI -0.24 to -0.09). Heterogeneity in baseline imbalances was present in six placebo- and five ezetimibe-comparisons. Heterogeneity was statistically significant for BMI, males, diabetics and hypertensives in the combined comparisons. There was a statistically significant preponderance for larger SDs in the PCSK9-inhibitor versus control groups (sign-test age 0.014; LDL-c 0.014; BMI 0.049). Meta-regression showed clinically relevant relationships of baseline imbalances in age, BMI and diabetics with the risk of any adverse events and the risk of mortality. Two relationships were statistically significant: A higher mean BMI in the drug versus control group with a decreased risk of mortality (beta - 0.56; 95% CI -1.10 to -0.02), and a higher proportion of diabetics with an increased risk of any adverse events (beta 0.02; 95% 0.01 to 0.04).
CONCLUSIONS
Heterogeneous baseline imbalances and systematically different SDs were present in evolocumab and alirocumab trials, so study groups cannot be assumed to be comparable. These findings raise concerns about the design and conduct of the randomization procedures.
Topics: Humans; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Cholesterol, LDL; Male; Anticholesteremic Agents; Randomized Controlled Trials as Topic; Female; Treatment Outcome; Middle Aged; Hypercholesterolemia; PCSK9 Inhibitors; Aged; Proprotein Convertase 9
PubMed: 38909176
DOI: 10.1186/s12874-024-02260-z -
Pathology, Research and Practice Jun 2024Cancer-associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts with various features in the cancer stroma and have been reported to influence cancer...
Cancer-associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts with various features in the cancer stroma and have been reported to influence cancer progression through cell-cell interactions in various types of malignancies, including lung adenocarcinoma (LUAD). Dipeptidyl peptidase 4 (DPP4) is a transmembrane protein with serine protease activity and is involved in the progression of tumors, metabolic diseases, and autoimmune diseases. In the present study, we focused on the role of DPP4-positive CAFs in LUAD. Immunohistochemistry revealed that 38 of 89 LUAD patients showed DPP4 expression in the fibrous stroma, and patients harboring DPP4-positive CAFs were more often male, had a higher Brinkman index, and had a higher Ki-67 labeling index of tumor cells than those with DPP4-negative CAFs. DPP4-positivity was associated with the expression of other CAF markers, α-SMA, periostin, and podoplanin, as well as a cellular senescence marker, p16. In the in vitro study, conditioned media collected from pulmonary fibroblast (OUS-11, HPF, and HPF-C)-induced overexpression of DPP4 significantly promoted the proliferation of LUAD cells (A549 and PC-9) and increased the expression levels of MCP-1, IL-8, IL-6, and GCSF in the media compared to those in controls. In addition, OUS-11 overexpression in DPP4 overexpression increased periostin expression. In conclusion, DPP4-positive CAFs could promote lung adenocarcinoma cell growth by producing soluble factors, and DPP4 inhibition may inhibit cancer progression.
PubMed: 38908333
DOI: 10.1016/j.prp.2024.155418