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Clinical Genetics Jul 2024Non-obstructive azoospermia (NOA) resulting from primary spermatogenic failure represents one of the most severe forms of male infertility, largely because therapeutic...
Non-obstructive azoospermia (NOA) resulting from primary spermatogenic failure represents one of the most severe forms of male infertility, largely because therapeutic options are very limited. Beyond their diagnostic value, genetic tests for NOA also hold prognostic potential. Specifically, genetic diagnosis enables the establishment of genotype-testicular phenotype correlations, which, in some cases, provide a negative predictive value for testicular sperm extraction (TESE), thereby preventing unnecessary surgical procedures. In this study, we employed whole-genome sequencing (WGS) to investigate two generations of an Iranian family with NOA and identified a homozygous splicing variant in TDRKH (NM_001083965.2: c.562-2A>T). TDRKH encodes a conserved mitochondrial membrane-anchored factor essential for piRNA biogenesis in germ cells. In Tdrkh knockout mice, de-repression of retrotransposons in germ cells leads to spermatogenic arrest and male infertility. Previously, our team reported TDRKH involvement in human NOA cases through the investigation of a North African cohort. This current study marks the second report of TDRKH's role in NOA and human male infertility, underscoring the significance of the piRNA pathway in spermatogenesis. Furthermore, across both studies, we demonstrated that men carrying TDRKH variants, similar to knockout mice, exhibit complete spermatogenic arrest, correlating with failed testicular sperm retrieval.
PubMed: 38956960
DOI: 10.1111/cge.14584 -
Protein and Peptide Letters Jul 2024Ubiquitination, a crucial post-translational modification, plays a role in nearly all physiological processes. Its functional execution depends on a series of catalytic...
Ubiquitination, a crucial post-translational modification, plays a role in nearly all physiological processes. Its functional execution depends on a series of catalytic reactions involving numerous proteases. TRIM26, a protein belonging to the TRIM family, exhibits E3 ubiquitin ligase activity because of its RING structural domain, and is present in diverse cell lineages. Over the last few decades, TRIM26 has been documented to engage in numerous physiological and pathological processes as a controller, demonstrating a diverse array of biological roles. Despite the growing research interest in TRIM26, there has been limited attention given to examining the protein's structure and function in existing reviews. This review begins with a concise overview of the composition and positioning of TRIM26 and then proceeds to examine its roles in immune response, viral invasion, and inflammatory processes. Simultaneously, we demonstrate the contribution of TRIM26 to the progression of various diseases, encompassing numerous malignancies and neurologic conditions. Finally, we have investigated the potential areas for future research on TRIM26.
PubMed: 38956921
DOI: 10.2174/0109298665311516240621114519 -
Endocrine, Metabolic & Immune Disorders... Jul 2024Mucoepidermoid Carcinoma (MEC) of the thyroid represents less than 0.5% of all thyroid neoplasms. Thyroglossal duct cyst carcinoma is a rare condition with only...
BACKGROUND
Mucoepidermoid Carcinoma (MEC) of the thyroid represents less than 0.5% of all thyroid neoplasms. Thyroglossal duct cyst carcinoma is a rare condition with only approximately 300 cases reported.
CASE REPORT
A 34-year-old pregnant woman at 37 weeks gestation presented to an endocrinological center for primary autoimmune hypothyroidism. The thyroid ultrasound revealed a pseudonodular pattern. The patient was followed up after two years. She reported a full-term delivery without complications. A new thyroid ultrasound was performed, showing a cystic lesion in the median suprathyroid area, measuring 6 x 9 x 10 mm, not previously reported. After 4 months, the suprathyroid cystic lesion was confirmed by thyroid ultrasound, measuring 6 x 11 x 12 mm. The patient was referred for fine-needle aspiration cytology. Cytological examination showed lymphocytes, red blood cells, and some epithelial aggregates with large cytoplasm and nuclear polymetrism with oxyphilic aspects. The patient underwent the Sistrunk procedure for the suprathyroid lesion. The histological examination revealed lymphocytic thyroiditis in heterotopic thyroid tissue with solid cell nest, epidermoid epithelium, and mucus-secreting cells suggestive of low-grade mucoepidermoid carcinoma. The immunohistochemistry study was positive, exhibiting thyroid transcription factor 1 and cytokeratin-19. No positivity was observed for thyroglobulin, calcitonin, galectin-3, and Hector Battifora mesothelial antigen 1. The recent follow-up examination, 13 months after the surgery, has been found negative for disease recurrence.
CONCLUSION
This is the first case of an MEC occurring within a thyroglossal duct. Considering the age of the patient, the histological diagnosis, and the absence of thyroid nodules and metastasis, we decided on the Sistrunk procedure without total thyroidectomy.
PubMed: 38956917
DOI: 10.2174/0118715303323033240620103828 -
CNS & Neurological Disorders Drug... Jul 2024Gliomas are the most frequent, heterogeneous group of tumors arising from glial cells, characterized by difficult monitoring, poor prognosis, and fatality. Tissue biopsy...
BACKGROUND
Gliomas are the most frequent, heterogeneous group of tumors arising from glial cells, characterized by difficult monitoring, poor prognosis, and fatality. Tissue biopsy is an established procedure for tumor cell sampling that aids diagnosis, tumor grading, and prediction of prognosis.
MATERIALS AND METHODS
We studied and compared the levels of liquid biopsy markers in patients with different grades of glioma. Also, we tried to prove the potential association between glioma and specific blood group antigens.
RESULTS
78 patients were found, among whom the maximum percentage with glioblastoma had blood group O+ (53.8%). The second highest frequency had blood group A+ (20.4%), followed by B+ (9.0%) and A- (5.1%), and the least with O-. Liquid biopsy biomarkers included Alanine Aminotransferase (ALT), Lactate Dehydrogenase (LDH), lymphocytes, Urea, Alkaline phosphatase (AST), Neutrophils, and C-Reactive Protein (CRP). The levels of all the components increased significantly with the severity of the glioma, with maximum levels seen in glioblastoma (grade IV), followed by grade III and grade II, respectively.
CONCLUSION
Gliomas have significant clinical challenges due to their progression with heterogeneous nature and aggressive behavior. A liquid biopsy is a non-invasive approach that aids in setting up the status of the patient and figuring out the tumor grade; therefore, it may show diagnostic and prognostic utility. Additionally, our study provides evidence to prove the role of ABO blood group antigens in the development of glioma. However, future clinical research on liquid biopsy will improve the sensitivity and specificity of these tests and confirm their clinical usefulness to guide treatment approaches.
.PubMed: 38956913
DOI: 10.2174/0118715273306577240612053957 -
Advanced Science (Weinheim,... Jul 2024Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the...
Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single-cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia-based intercellular communication hub consisting of malignant cells, ALCAM macrophages, and exhausted CD8 T cells around the tumor boundary. A hypoxic microenvironment promotes binding of HIF-1α complex is demonstrated to the ALCAM promoter therefore increasing its expression in macrophages, and the ALCAM macrophages co-localize with exhausted CD8 T cells in the tumor spatial microenvironment and promote T cell exhaustion. Preclinically, HIF-1ɑ inhibition reduces ALCAM expression in macrophages and exhausted CD8 T cells and potentiates T cell antitumor function to enhance immunotherapy efficacy. This study reveals the systematic landscape of hypoxia at single-cell resolution and spatial architecture and highlights the effect of hypoxia on immunotherapy resistance through the ALCAM macrophage-exhausted T cell axis, providing a novel immunotherapeutic strategy to overcome hypoxia-induced resistance in cancers.
PubMed: 38956900
DOI: 10.1002/advs.202309885 -
Thoracic Cancer Jul 2024A 61-year-old man presented to our hospital with a chief complaint of chronic cough. He was diagnosed with lung squamous cell carcinoma at clinical stage cT2aN3M1a. He...
A 61-year-old man presented to our hospital with a chief complaint of chronic cough. He was diagnosed with lung squamous cell carcinoma at clinical stage cT2aN3M1a. He received chemotherapy up to the fourth line, but both the primary tumor and lymph node metastases increased in size. Nivolumab, administered as the fifth line, resulted in a complete response (CR) that continued for 2 years and 8 months. Treatment was stopped due to the appearance of common terminology criteria for adverse events grade 1 pneumonitis. He was followed up without treatment for 3 years and 8 months, but a left supraclavicular fossa lymph node metastasis appeared. Retreatment with nivolumab was initiated, and the patient achieved CR again. One year and 6 months after retreatment, CR was maintained with nivolumab. This case represents a rare instance in which nivolumab yielded a significant response after a prolonged immune checkpoint inhibitor (ICI)-free interval. Our experience has shown that the long-term response to ICIs may deteriorate in the future. Therefore, retreatment with ICIs may be effective when the initial therapy is successful.
PubMed: 38956899
DOI: 10.1111/1759-7714.15267 -
Amyloid : the International Journal of... Jul 2024Daratumumab's incorporation in the upfront treatment of light chain (AL) amyloidosis has led to daratumumab (dara) refractoriness early in disease course. Patients who...
BACKGROUND
Daratumumab's incorporation in the upfront treatment of light chain (AL) amyloidosis has led to daratumumab (dara) refractoriness early in disease course. Patients who experience relapse or have suboptimal response to dara-based-therapy, have limited options.
OBJECTIVE
This study aimed to evaluate the outcomes of venetoclax-based therapy in t(11;14) positive AL patients who previously failed dara.
METHODS
Thirty-one patients with AL were included in this bi-institutional retrospective analysis.
RESULTS
Dara failure was due to inadequate response in 20 (65%) patients, haematologic relapse in 7 (22%), and both haematologic plus organ relapse in 4 (13%). Overall haematologic response rate to venetoclax-based therapy was 97%, with ≥ VGPR being 91%. Of the 19 evaluable patients with cardiac involvement, 14 (74%) achieved organ response. Of the 13 evaluable patients with renal involvement, 6 (46%) achieved organ response. With a median follow-up of 22 months, median time-to-next-treatment (TTNT) and overall survival (OS) were not reached. The 12- and 24-month TTNT rates were 74% and 56%, respectively. At data-cut-off, four patients had died, all from AL-related organ complications. The 12- and 24-month OS rates were 89% and 85%, respectively. Grade ≥3 adverse events occurred in 26% of patients, with 6% due to infections.
CONCLUSION
These findings are encouraging for the use of venetoclax as salvage therapy post-dara failure.
PubMed: 38956891
DOI: 10.1080/13506129.2024.2366806 -
MAbs 2024Precise measurement of the binding activity changes of therapeutic antibodies is important to determine the potential critical quality attributes (CQAs) in...
Early determination of potential critical quality attributes of therapeutic antibodies in developability studies through surface plasmon resonance-based relative binding activity assessment.
Precise measurement of the binding activity changes of therapeutic antibodies is important to determine the potential critical quality attributes (CQAs) in developability assessment at the early stage of antibody development. Here, we report a surface plasmon resonance (SPR)-based relative binding activity method, which incorporates both binding affinity and binding response and allows us to determine relative binding activity of antibodies with high accuracy and precision. We applied the SPR-based relative binding activity method in multiple forced degradation studies of antibody developability assessment. The current developability assessment strategy provided comprehensive, precise characterization of antibody binding activity in the stability studies, enabling us to perform correlation analysis and establish the structure-function relationship between relative binding activity and quality attributes. The impact of a given quality attribute on binding activity could be confidently determined without isolating antibody variants. We identified several potential CQAs, including Asp isomerization, Asn deamidation, and fragmentation. Some potential CQAs affected binding affinity of antibody and resulted in a reduction of binding activity. Certain potential CQAs impaired antibody binding to antigen and led to a loss of binding activity. A few potential CQAs could influence both binding affinity and binding response and cause a substantial decrease in antibody binding activity. Specifically, we identified low abundance Asn33 deamidation in the light chain complementarity-determining region as a potential CQA, in which all the stressed antibody samples showed Asn33 deamidation abundances ranging from 4.2% to 27.5% and a mild binding affinity change from 1.76 nM to 2.16 nM.
Topics: Surface Plasmon Resonance; Humans; Antibodies, Monoclonal; Antibody Affinity; Protein Binding; Animals
PubMed: 38956880
DOI: 10.1080/19420862.2024.2374607 -
Annals of Medicine Dec 2024Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in women of reproductive age. It is frequently comorbid with obesity and...
BACKGROUND
Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in women of reproductive age. It is frequently comorbid with obesity and negative emotions. Currently, there are few reports on the relationship between obesity and negative emotions in patients with PCOS. Here we performed both basic and clinical studies to study the relationship between obesity and negative emotions in PCOS.
METHODS
We performed a cross-sectional study including 608 patients with PCOS and 184 healthy participants to assess the mental health status of people with different body mass indices (BMI). Self-rated anxiety, depression, and perceived stress scales were used for subjective mood evaluations. Rat PCOS models fed 45 and 60% high-fat diets were used to confirm the results of the clinical study. Elevated plus maze and open field tests were used to assess anxiety- and depression-like behaviors in rats.
RESULTS
We observed overweight/obesity, increased depression, anxiety, and perceived stress in women with PCOS, and found that anxiety and depression were negatively correlated with BMI in patients with severe obesity and PCOS. Similar results were confirmed in the animal study; the elevated plus maze test and open field test demonstrated that only 60% of high fat diet-induced obesity partly reversed anxiety- and depression-like behaviors in PCOS rats. A high-fat diet also modulated rat hypothalamic and hippocampal luteinizing hormone and testosterone levels.
CONCLUSION
These results reveal a potential relationship between obesity and negative emotions in PCOS and prompt further investigation. The interactions between various symptoms of PCOS may be targeted to improve the overall well-being of patients.
Topics: Polycystic Ovary Syndrome; Female; Animals; Humans; Obesity; Rats; Cross-Sectional Studies; Adult; Anxiety; Depression; Body Mass Index; Diet, High-Fat; Disease Models, Animal; Rats, Sprague-Dawley; Young Adult; Emotions; Stress, Psychological
PubMed: 38956857
DOI: 10.1080/07853890.2024.2373199 -
Scandinavian Journal of Psychology Jul 2024Cancer survivors may be struggling to re-create meaning in life. Addressing their personal sources of meaning can support them in this process. The sources of meaning...
Cancer survivors may be struggling to re-create meaning in life. Addressing their personal sources of meaning can support them in this process. The sources of meaning card method (SoMeCaM) aims to map and explore personal sources of meaning in a 1-h session. It includes 26 cards, each with a statement on a source of meaning. The purpose of this study was to validate the statements on the sources of meaning cards for use among participants in cancer rehabilitation by examining whether participants attribute the same meaning to the statements as intended. The three step test interview method was used to assess response processes to the sources of meaning cards among 12 participants in a 5-day cancer rehabilitation program in Denmark. The interviews were transcribed verbatim and analyzed using framework analysis. Nineteen of the 26 statements were interpreted congruently, that is, in line with the underlying theory, by all participants. Issues of incongruency, ambiguity and confusion were observed in participants' interpretations of the statements on religiosity (n = 6), spirituality (n = 10), and reason (n = 6). Minor issues were observed for the statements on practicality, achievement, knowledge, and attentiveness. In most statements, cancer survivors' interpretation aligned with the underlying theory. Problems were apparent regarding the sources of meaning religiosity, spirituality and reason, and a reconsideration of the wording of the statements is recommended. These problems may be due to cultural and linguistic interpretations rather than to being a cancer survivor. Future studies could focus on these issues in other target populations. Despite these minor issues, the SoMeCaM has proven useful in addressing the important topic of meaning in life in the cancer rehabilitation setting. Clinicians should pay attention to nuances in participants' understanding of the cards.
PubMed: 38956815
DOI: 10.1111/sjop.13048