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Molecules (Basel, Switzerland) Feb 2024Bitespiramycin, has been shown to have a therapeutic effect against respiratory tract inflammation, including a potential effect against COVID-19. A current clinical...
Bitespiramycin, has been shown to have a therapeutic effect against respiratory tract inflammation, including a potential effect against COVID-19. A current clinical trial in China showed that bitespiramycin was an effective treatment for severe pneumonia and intracranial infection. However, there is lack of an analytical method to elucidate the distribution of bitespiramycin. In this study, a highly sensitive, rapid and reliable UPLC-MS/MS method was developed to comprehensively characterize the bitespiramycin distribution in various bio-samples, which is significantly improved upon the published work. A rapid sample preparation method was developed by using -butanol as the solvent to extract bitespiramycin from different bio-samples. The extract was then directly analyzed by UPLC-MS/MS coupled with an alkaline-resistant column after centrifugation which avoids the time-consuming concentration process under nitrogen and redissolution. The method was employed to accurately quantify bitespiramycin and its metabolites in rat plasma, tissues, and human cerebrospinal fluid. Notably, the presence of bitespiramycin and its metabolites was identified for the first time in various rat organs including brain, testis, bladder and prostate as well as in human cerebrospinal fluid. This newly developed approach shows great promise for drug distribution assays including other antibiotics and can help elucidate the ADME of bitespiramycin.
Topics: Male; Rats; Humans; Animals; Chromatography, Liquid; Liquid Chromatography-Mass Spectrometry; Tandem Mass Spectrometry; Spiramycin; Chromatography, High Pressure Liquid
PubMed: 38474552
DOI: 10.3390/molecules29051037 -
BMC Cancer Mar 2024Liquid biopsy can detect circulating cancer cells or tumor cell-derived DNA at various stages of cancer. The fluid from these biopsies contains extracellular vesicles... (Review)
Review
Liquid biopsy can detect circulating cancer cells or tumor cell-derived DNA at various stages of cancer. The fluid from these biopsies contains extracellular vesicles (EVs), such as apoptotic bodies, microvesicles, exomeres, and exosomes. Exosomes contain proteins and nucleic acids (DNA/RNA) that can modify the microenvironment and promote cancer progression, playing significant roles in cancer pathology. Clinically, the proteins and nucleic acids within the exosomes from liquid biopsies can be biomarkers for the detection and prognosis of cancer. We review EVs protein and miRNA biomarkers identified for select cancers, specifically melanoma, glioma, breast, pancreatic, hepatic, cervical, prostate colon, and some hematological malignancies. Overall, this review demonstrates that EV biomolecules have great potential to expand the diagnostic and prognostic biomarkers used in Oncology; ultimately, EVs could lead to earlier detection and novel therapeutic targets. Clinical implicationsEVs represent a new paradigm in cancer diagnostics and therapeutics. The potential use of exosomal contents as biomarkers for diagnostic and prognostic indicators may facilitate cancer management. Non-invasive liquid biopsy is helpful, especially when the tumor is difficult to reach, such as in pancreatic adenocarcinoma. Moreover, another advantage of using minimally invasive liquid biopsy is that monitoring becomes more manageable. Identifying tumor-derived exosomal proteins and microRNAs would allow a more personalized approach to detecting cancer and improving treatment.
Topics: Male; Humans; Adenocarcinoma; Pancreatic Neoplasms; Extracellular Vesicles; Exosomes; MicroRNAs; Biomarkers; DNA; Biomarkers, Tumor; Tumor Microenvironment
PubMed: 38454346
DOI: 10.1186/s12885-024-11819-4 -
Nature Reviews. Disease Primers Mar 2024Alkaptonuria is a rare inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase activity. The consequent homogentisic acid (HGA) accumulation... (Review)
Review
Alkaptonuria is a rare inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase activity. The consequent homogentisic acid (HGA) accumulation in body fluids and tissues leads to a multisystemic and highly debilitating disease whose main features are dark urine, ochronosis (HGA-derived pigment in collagen-rich connective tissues), and a painful and severe form of osteoarthropathy. Other clinical manifestations are extremely variable and include kidney and prostate stones, aortic stenosis, bone fractures, and tendon, ligament and/or muscle ruptures. As an autosomal recessive disorder, alkaptonuria affects men and women equally. Debilitating symptoms appear around the third decade of life, but a proper and timely diagnosis is often delayed due to their non-specific nature and a lack of knowledge among physicians. In later stages, patients' quality of life might be seriously compromised and further complicated by comorbidities. Thus, appropriate management of alkaptonuria requires a multidisciplinary approach, and periodic clinical evaluation is advised to monitor disease progression, complications and/or comorbidities, and to enable prompt intervention. Treatment options are patient-tailored and include a combination of medications, physical therapy and surgery. Current basic and clinical research focuses on improving patient management and developing innovative therapies and implementing precision medicine strategies.
Topics: Male; Humans; Female; Alkaptonuria; Quality of Life; Ochronosis; Kidney; Homogentisic Acid
PubMed: 38453957
DOI: 10.1038/s41572-024-00498-x -
Retinal Cases & Brief Reports Mar 2024To describe a vision-threatening adverse event of a novel CAR T-cell immunotherapy for metastatic prostate cancer.
PURPOSE
To describe a vision-threatening adverse event of a novel CAR T-cell immunotherapy for metastatic prostate cancer.
METHODS
Observational Case Report.
PATIENT
77-year-old male with history of metastatic prostate cancer and pulmonary embolism enrolled in a clinical trial investigating the use of CAR T-cell immunotherapy for treatment of metastatic prostate cancer presented with a subjective left temporal visual disturbance.
RESULTS
The patient was found to have bilateral extensive choroidal detachments on examination. OCT macula demonstrated no intraretinal fluid or supraretinal fluid in both eyes. B-scan of both eyes redemonstrated choroidal detachments in both eyes and no retinal detachment in either eye. The patient was initiated on a topical and systemic steroid regimen and experienced symptomatic and clinical improvement.
CONCLUSION
We exhibit a case of bilateral choroidal detachments secondary to systemic reaction to a novel immunotherapy for metastatic cancer successfully treated with systemic and topical steroids. Close follow up may be required for patients receiving similar novel immunotherapeutic regimens.
PubMed: 38437821
DOI: 10.1097/ICB.0000000000001558 -
Cancer Cell International Feb 2024Cancer chemoresistance is a problematic dilemma that significantly restrains numerous cancer management protocols. It can promote cancer recurrence, spreading of cancer,... (Review)
Review
Cancer chemoresistance is a problematic dilemma that significantly restrains numerous cancer management protocols. It can promote cancer recurrence, spreading of cancer, and finally, mortality. Accordingly, enhancing the responsiveness of cancer cells towards chemotherapies could be a vital approach to overcoming cancer chemoresistance. Tumour cells express a high level of sphingosine kinase-1 (SphK1), which acts as a protooncogenic factor and is responsible for the synthesis of sphingosine-1 phosphate (S1P). S1P is released through a Human ATP-binding cassette (ABC) transporter to interact with other phosphosphingolipids components in the interstitial fluid in the tumor microenvironment (TME), provoking communication, progression, invasion, and tumor metastasis. Also, S1P is associated with several impacts, including anti-apoptotic behavior, metastasis, mesenchymal transition (EMT), angiogenesis, and chemotherapy resistance. Recent reports addressed high levels of S1P in several carcinomas, including ovarian, prostate, colorectal, breast, and HCC. Therefore, targeting the S1P/SphK signaling pathway is an emerging therapeutic approach to efficiently attenuate chemoresistance. In this review, we comprehensively discussed S1P functions, metabolism, transport, and signaling. Also, through a bioinformatic framework, we pointed out the alterations of SphK1 gene expression within different cancers with their impact on patient survival, and we demonstrated the protein-protein network of SphK1, elaborating its sparse roles. Furthermore, we made emphasis on different machineries of cancer resistance and the tight link with S1P. We evaluated all publicly available SphK1 inhibitors and their inhibition activity using molecular docking and how SphK1 inhibitors reduce the production of S1P and might reduce chemoresistance, an approach that might be vital in the course of cancer treatment and prognosis.
PubMed: 38419070
DOI: 10.1186/s12935-024-03221-8 -
Basic & Clinical Pharmacology &... May 2024Although α-adrenoceptor (α-AR) antagonists used to treat benign prostatic hyperplasia can cause ejaculation disorders, the aetiology of this adverse event is still...
Although α-adrenoceptor (α-AR) antagonists used to treat benign prostatic hyperplasia can cause ejaculation disorders, the aetiology of this adverse event is still controversial. Therefore, we investigated the effects of antagonists with different affinities for α-AR subtypes on ejaculatory function and their mechanisms of action in normal rats. In the spontaneous seminal emission (SSE) test, systemically administered prazosin, terazosin, tamsulosin and naftopidil decreased the weight of ejaculated seminal material in a dose-dependent manner; the potency order was as follows: tamsulosin > terazosin > prazosin > naftopidil. The selective α-AR antagonist BMY7378 had no effect on SSE. Intrathecal tamsulosin and naftopidil did not inhibit SSE. Tamsulosin, the most potent, was ineffective as a single dose and significantly increased seminal vesicle fluid in rats treated for 2 weeks but did not significantly change retrograde ejaculation. These results indicated that the difference in inhibitory potency of the five α-AR antagonists against SSE was due to the involvement of α-AR subtypes. Our results further suggested that α-AR antagonist-induced ejaculatory dysfunction at the peripheral level was mainly due to the loss of seminal emission, although some retrograde ejaculation may also be involved.
Topics: Male; Rats; Animals; Tamsulosin; Adrenergic alpha-1 Receptor Antagonists; Ejaculatory Dysfunction; Sulfonamides; Prazosin; Receptors, Adrenergic, alpha-1; Adrenergic alpha-Antagonists; Naphthalenes; Piperazines
PubMed: 38409579
DOI: 10.1111/bcpt.13993 -
American Family Physician Feb 2024An acute uncomplicated urinary tract infection (UTI) is a bacterial infection of the lower urinary tract with no sign of systemic illness or pyelonephritis in a...
An acute uncomplicated urinary tract infection (UTI) is a bacterial infection of the lower urinary tract with no sign of systemic illness or pyelonephritis in a noncatheterized, nonpregnant adult with no urologic abnormalities or immunocompromise. In women, a self-diagnosis of a UTI with the presence of typical symptoms (e.g., frequency, urgency, dysuria/burning sensation, nocturia, suprapubic pain), without vaginal discharge, is accurate enough to diagnose an uncomplicated UTI without further testing. Urine culture and susceptibility testing should be reserved for women with recurrent infection, treatment failure, history of resistant isolates, or atypical presentation to make a definitive diagnosis and guide antibiotic selection. First-line antibiotics include nitrofurantoin for five days, fosfomycin in a single dose, trimethoprim for three days, or trimethoprim/sulfamethoxazole for three days. Symptomatic treatment with nonsteroidal anti-inflammatory drugs and delayed antibiotics may be considered because the risk of complications is low. Increased fluids, intake of cranberry products, and methenamine hippurate can prevent recurrent infections. Antibiotic prophylaxis is also effective in preventing recurrence but has a risk of adverse effects and antimicrobial resistance. Men with lower UTI symptoms should always receive antibiotics, with urine culture and susceptibility results guiding the antibiotic choice. Clinicians should also consider the possibility of urethritis and prostatitis in men with UTI symptoms. First-line antibiotics for men with uncomplicated UTI include trimethoprim, trimethoprim/sulfamethoxazole, and nitrofurantoin for seven days. Uncomplicated UTIs in nonfrail women and men 65 years and older with no relevant comorbidities also necessitate a urine culture with susceptibility testing to adjust the antibiotic choice after initial empiric treatment; first-line antibiotics and treatment durations do not differ from those recommended for younger adults.
Topics: Adult; Female; Humans; Male; Anti-Bacterial Agents; Fosfomycin; Nitrofurantoin; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections
PubMed: 38393801
DOI: No ID Found -
Bioengineering (Basel, Switzerland) Jan 2024Whole-Body Diffusion-Weighted Imaging (WBDWI) is an established technique for staging and evaluating treatment response in patients with multiple myeloma (MM) and...
Deep Learning for Delineation of the Spinal Canal in Whole-Body Diffusion-Weighted Imaging: Normalising Inter- and Intra-Patient Intensity Signal in Multi-Centre Datasets.
BACKGROUND
Whole-Body Diffusion-Weighted Imaging (WBDWI) is an established technique for staging and evaluating treatment response in patients with multiple myeloma (MM) and advanced prostate cancer (APC). However, WBDWI scans show inter- and intra-patient intensity signal variability. This variability poses challenges in accurately quantifying bone disease, tracking changes over follow-up scans, and developing automated tools for bone lesion delineation. Here, we propose a novel automated pipeline for inter-station, inter-scan image signal standardisation on WBDWI that utilizes robust segmentation of the spinal canal through deep learning.
METHODS
We trained and validated a supervised 2D U-Net model to automatically delineate the spinal canal (both the spinal cord and surrounding cerebrospinal fluid, CSF) in an initial cohort of 40 patients who underwent WBDWI for treatment response evaluation (80 scans in total). Expert-validated contours were used as the target standard. The algorithm was further semi-quantitatively validated on four additional datasets (three internal, one external, 207 scans total) by comparing the distributions of average apparent diffusion coefficient (ADC) and volume of the spinal cord derived from a two-component Gaussian mixture model of segmented regions. Our pipeline subsequently standardises WBDWI signal intensity through two stages: (i) normalisation of signal between imaging stations within each patient through histogram equalisation of slices acquired on either side of the station gap, and (ii) inter-scan normalisation through histogram equalisation of the signal derived within segmented spinal canal regions. This approach was semi-quantitatively validated in all scans available to the study (N = 287).
RESULTS
The test dice score, precision, and recall of the spinal canal segmentation model were all above 0.87 when compared to manual delineation. The average ADC for the spinal cord (1.7 × 10 mm/s) showed no significant difference from the manual contours. Furthermore, no significant differences were found between the average ADC values of the spinal cord across the additional four datasets. The signal-normalised, high-b-value images were visualised using a fixed contrast window level and demonstrated qualitatively better signal homogeneity across scans than scans that were not signal-normalised.
CONCLUSION
Our proposed intensity signal WBDWI normalisation pipeline successfully harmonises intensity values across multi-centre cohorts. The computational time required is less than 10 s, preserving contrast-to-noise and signal-to-noise ratios in axial diffusion-weighted images. Importantly, no changes to the clinical MRI protocol are expected, and there is no need for additional reference MRI data or follow-up scans.
PubMed: 38391616
DOI: 10.3390/bioengineering11020130 -
Environmental Pollution (Barking, Essex... Apr 2024The harmful effects of microplastics (MPs) on male fertility are receiving more and more attention. However, the impact of low-dose MPs exposure on the reproductive...
The harmful effects of microplastics (MPs) on male fertility are receiving more and more attention. However, the impact of low-dose MPs exposure on the reproductive function of male mice is still unclear. In this study, we exposed male mice to low-dose MPs (25-30 μg/kg body weight/day) or low-dose MPs combined with high-fat diet (HFD) feeding. Our results showed that low-dose MPs exposure or HFD feeding significantly reduced sperm quality and the number of offspring born, while low-dose MPs exposure combined with HFD feeding further enhanced the above effects. The combination of low-dose MPs exposure and HFD feeding resulted in a notable elevation of inflammatory level within the prostate of mice and induced apoptosis of prostate epithelium and a decrease in nutrients (zinc, citrate) in seminal plasma fluid. Our findings in this study could provide valuable clues for better understanding the influence of low-dose MPs exposure on the reproductive system under metabolic disorders and facilitate the development of the prevention of reproductive toxicity caused by MPs exposure.
Topics: Male; Humans; Polystyrenes; Microplastics; Plastics; Diet, High-Fat; Prostate; Semen; Fertility; Obesity
PubMed: 38367694
DOI: 10.1016/j.envpol.2024.123567 -
BMC Anesthesiology Feb 2024The development of endoscopic systems that include bipolar electrocautery has enabled the use of normal saline irrigation in transurethral or transcervical endoscopic...
BACKGROUND
The development of endoscopic systems that include bipolar electrocautery has enabled the use of normal saline irrigation in transurethral or transcervical endoscopic surgery. However, excessive saline absorption can cause hyperchloremic metabolic acidosis.
CASE PRESENTATION
Patient 1: A 76-year-old man was scheduled for transurethral resection of the prostate with saline irrigation. Approximately 140 min after the surgery, abdominal distension and cervical edema were observed. Abdominal ultrasound examination indicated a subhepatic hypoechoic lesion, which suggested extravasation of saline. Arterial blood gas analysis revealed hyperchloremic metabolic acidosis. The patient was extubated 2 h after the operation with no subsequent airway problems, and the electrolyte imbalance was gradually corrected. Patient 2: A 43-year-old woman was scheduled for transcervical resection of a uterine fibroid with saline irrigation. When the drape was removed after the operation was finished, notable upper extremity edema was observed. Arterial blood gas analysis revealed hyperchloremic metabolic acidosis. The patient's acidemia, electrolyte imbalance, and neck edema gradually resolved, and the patient was extubated 16 h after the operation without subsequent airway problems.
CONCLUSIONS
Anesthesiologists should be aware of acidemia, cardiopulmonary complications, and airway obstruction caused by excessive saline absorption after saline irrigation in endoscopic surgery.
Topics: Male; Female; Humans; Adult; Aged; Transurethral Resection of Prostate; Saline Solution; Acidosis; Electrolytes; Edema; Therapeutic Irrigation
PubMed: 38341531
DOI: 10.1186/s12871-024-02437-5