Search

Background: Hereditary Sensory Motor Neuropathy (HSMN) 1A and Multiple Sclerosis (MS) are distinct demyelinating disorders affecting the peripheral and central nervous systems, respectively. We present a case of simultaneous occurrence of both conditions, exploring the clinical presentation, diagnostic workup, and potential interplay between these diseases. Case presentation and clinical approach: A 49-year-old male with a history of optic neuritis presented with progressive numbness, weakness, and sensory loss in all extremities over four years. Neurological examination revealed distal weakness, sensory deficits in a stocking-glove distribution, pes cavus, and hammer toes. Nerve conduction studies and electromyography confirmed sensory motor demyelinating polyneuropathy. The patient's lack of response to intravenous immunoglobulin therapy suggested hereditary neuropathy as an etiology. Genetic testing identified a PMP22 gene duplication, confirming HSMN 1A. Elevated cerebrospinal fluid protein level and oligoclonal bands, combined with magnetic resonance of the brain showing multiple T2 hyperintense lesions in the brain and spinal cord, fulfilled the diagnostic criteria for MS. Discussion: This case of co-existing HSMN 1A and MS highlights a rare overlap of peripheral and central demyelination. While HSMN 1A results from PMP22 gene duplication, primarily affecting peripheral myelin, MS is driven by immune-mediated central myelin attacks. The co-existence of these disorders suggests potential shared mechanisms, such as immune dysregulation. Some evidence suggests that overexpression of PMP22 in HSMN 1A may disturb immune tolerance, possibly triggering autoimmune responses linked to MS. Further research is needed to explore the genetic and autoimmune interplay between these two diseases, expanding our understanding of demyelinating disorders. [ABSTRACT FROM AUTHOR]

IMP dehydrogenase (IMPDH) inhibition has emerged as a new target therapy for glioblastoma multiforme (GBM), which remains one of the most refractory tumors to date. TCGA analyses revealed distinct expression profiles of IMPDH isoenzymes in various subtypes of GBM and low-grade glioma (LGG). To dissect the mechanism(s) underlying the anti-tumor effect of IMPDH inhibition in adult GBM, we investigated how mycophenolic acid (MPA, an IMPDH inhibitor) treatment affected key oncogenic drivers in glioblastoma cells. Our results showed that MPA decreased the expression of telomerase reverse transcriptase (TERT) in both U87 and U251 cells, and the expression of O6-methylguanine-DNA methyltransferase (MGMT) in U251 cells. In support, MPA treatment reduced the amount of telomere repeats in U87 and U251 cells. TERT downregulation by MPA was associated with a significant decrease in c-Myc (a TERT transcription activator) in U87 but not U251 cells, and a dose-dependent increase in p53 and CCCTC-binding factor (CTCF) (TERT repressors) in both U87 and U251 cells. In U251 cells, MPA displayed strong cytotoxic synergy with BCNU and moderate synergy with irinotecan, oxaliplatin, paclitaxel, or temozolomide (TMZ). In U87 cells, MPA displayed strong cytotoxic synergy with all except TMZ, acting primarily through the apoptotic pathway. Our work expands the mechanistic potential of IMPDH inhibition to TERT/telomere regulation and reveals a synthetic lethality between MPA and anti-GBM drugs. [ABSTRACT FROM AUTHOR]

Byline: Michael Chih-Hung Wang, Lily Shui-Lien Chen, Julian Ming-Sung Cheng, Laura Hsing-Jung Wu The emergence of e-commerce has led to the implementation of e-channels of distribution. Although research determines the factors influencing the implementation of e-channels of distribution, since the performance of internet adoption as a channel of distribution has fallen short of expectations and owing to the diversity of the e-commerce environment, the factors leading to high (i.e., success) and low performance (i.e., failure) may differ. Following a robust literature review, this study identified the factors of the implementation of electronic distribution channels. An online survey performed in Taiwan yielded 106 valid responses (electronic retailers). Correlation analysis confirmed that the success and failure factors for the implementation of e-channels of distribution differ between two different types of electronic distribution channels - transactional e-commerce websites and partnership e-commerce websites.

Pancreatic ductal adenocarcinoma (PDAC) has an immunosuppressed, apoptosis-resistant phenotype. TLY012 is pegylated recombinant Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL), an orphan drug for chronic pancreatitis and systemic sclerosis. Innate immune TRAIL signaling suppresses cancer. We hypothesized that the combination of immune checkpoint-blocking anti-PD-1 antibody and TLY012 would have synergistic anti-tumor efficacy in immune-competent PDAC-bearing mice. PDAC tumor-bearing C57Bl/6 mice treated with 10 mg/kg anti-mouse PD-1 antibody twice weekly and 10 mg/kg TLY012 three times weekly had reduced tumor growth and tumor volume at 70 days compared to either drug alone (all P < 0.005). B-cell activating factor (BAFF), which promotes PDAC tumors, decreased to 44% of control mice with dual treatment at 7 days and remained decreased at 3 months. Long-term dual treatment showed the highest plasma levels of proinflammatory cytokines interferon-gamma (average 5.6 times control level, P=0.046), CCL5 (average 14.1 times control level, P=0.048), and interleukin-3 (IL-3, average 71.1 times control level, P=0.0053). Flow cytometry showed trends toward decreased circulating regulatory T cells, increased NK cells, and a higher proportion of CD8+ T cells within tumors in the dual treatment group. In summary, the combination of anti-PD-1 and TLY012 prevented the growth of PDAC in an immunocompetent mouse model while increasing tumor-infiltrating CD8+ T cells, decreasing circulating T-regulatory cells and altering plasma cytokine expression of CCL5, interferon-gamma, and IL-3 to promote proinflammatory, antitumor effects. Combining TLY012 and anti-mouse PD-1 modifies immune cell and cytokine levels to induce a more proinflammatory immune environment that contributes to decreased PDAC tumor growth., Competing Interests: W.S.E-D. is the Scientific Founder of Oncoceutics, Inc., a subsidiary of Chimerix, and Founder of p53-Therapeutics, Inc., and SMURF-Therapeutics, Inc. Dr. El-Deiry has disclosed his relationships and potential conflict of interest to his academic institution/employer and is fully compliant with NIH and institutional policy that is managing this potential conflict of interest. The disclosed relationships by W.S.E-D. are not directly relevant to the present manuscript as none of the treatments used are owned or licensed by the entities he founded. S.L. is co-Founder, CEO and Chairman of D&D Pharmatech., (AJCR Copyright © 2025.)

Androgen receptor (AR) signaling is a target in prostate cancer therapy and can be treated with non-steroidal anti-androgens (NSAA) including enzalutamide, and apalutamide for patients with advanced disease. Metastatic castration-resistant prostate cancer (mCPRC) develop resistance becomes refractory to therapy limiting patient overall survival. Darolutamide is a novel next-generation androgen receptor-signaling inhibitor that is FDA approved for non-metastatic castration resistant prostate cancer (nmCRPC). Imipridone ONC201/TIC10 is first-in-class small molecule imipridone that activates the integrated stress response (ISR), upregulates TNF-related apoptosis-inducing ligand (TRAIL) and has activity against CRPC alone or in combination with enzalutamide in preclinical models. We hypothesized that combination of imipridones with androgen receptor signaling blockers such as darolutamide may synergize in anti-tumor efficacy against mCRPC cells. mCRPC cell lines 22RV1, LNCaP, DU145 and PC3 were treated with imipridones ONC201, ONC206, apalutamide, darolutamide, or enzalutamide as single agents or in combinations. Combinations of ONC201 or ONC206 and androgen receptor signaling blockers demonstrated synergistic effects in mCRPC cells. Combinations of ONC201 and darolutamide or enzalutamide reduced PSA levels in LNCaP cells and induced of ATF4 in both LNCaP and 22RV1 cell lines. Darolutamide synergized with ONC201 regardless of AR status or castration sensitivity in vitro . Flow cytometric analysis showed increased intra-tumoral NK cells in mice treated with ONC201 and combination of ONC201 and darolutamide. Trends of increased TRAIL activation within NK cells were also observed in treatment groups. ONC201 and darolutamide demonstrated anti-tumor effects in vivo in the 22RV1 CRPC model. Our results prompt further translational and clinical studies with imipridones ONC201 or ONC206 in combination with enzalutamide or darolutamide for treatment of castrate resistant advanced or metastatic prostate cancer., Competing Interests: W.S.E-D. is a co-founder of Oncoceutics, Inc., a subsidiary of Chimerix. Dr. El-Deiry has disclosed his relationship with Oncoceutics/Chimerix and potential conflict of interest to his academic institution/employer and is fully compliant with NIH and institutional policy that is managing this potential conflict of interest., (AJCR Copyright © 2024.)

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a central nervous system demyelinating disease that has become a major source of morbidity among children and adults. In the first case, we present an 18-year-old Hispanic female with a recently resolved upper respiratory infection who presented with fever, headache, progressive quadriparesis, urinary retention, and encephalopathy. The hospital course involved autonomic dysfunction and prolonged intubation requiring tracheostomy and gastrostomy. Cerebrospinal fluid (CSF) showed pleocytosis and a positive MOG titer (1:40). Magnetic resonance imaging (MRI) showed longitudinally extensive cervicothoracic T2 hyperintensity and brain multifocal T2 hyperintensities. After high-dose intravenous methylprednisolone (IVMP) and intravenous immunoglobulin (IVIG), she had full neurological recovery by the last follow-up. The second case is of a 22-year-old Hispanic male who presented with progressive lower extremity paresthesia and weakness over six weeks. CSF demonstrated pleocytosis, elevated protein, oligoclonal bands, and MOG antibody. MRI revealed multiple subcortical T2-hyperintense lesions and enhancing midcervical and lower thoracic lesions. Treatment with IVMP led to minor improvement with discharge on steroid taper and azathioprine. The patient's disease progressed with a fluctuating course requiring two readmissions with upper extremity weakness, right optic neuritis, and urinary sphincteric dysfunction with neuroradiologic worsening. Treatment throughout multiple admissions included intravenous steroids, IVIG, plasmapheresis, mycophenolate mofetil, and rituximab with minimal improvement, symptom recurrence, and progression of multifocal lesions. The patient died four months after the symptom onset. These cases had markedly different treatment responses despite similar baseline characteristics. The difference in morbidity and disability burden highlights the importance of further investigation of this condition through clinical trials., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Human Research Protection Program Institutional Review Board issued approval N/A. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Frade et al.)

The mammalian nucleolar proteins nucleostemin and GNL3-like (GNL3L) are encoded by paralogous genes that arose from an ancestral invertebrate gene, GNL3. Invertebrate GNL3 has been implicated in ribosome biosynthesis, as has its mammalian descendent, GNL3L. The paralogous mammalian nucleostemin protein has, instead, been implicated in cell renewal. Here, we found that depletion of nucleostemin in a human breast carcinoma cell line triggers prompt and significant DNA damage in S-phase cells without perturbing the initial step of ribosomal (r)RNA synthesis and only mildly affects the total ribosome production. By contrast, GNL3L depletion markedly impairs ribosome production without inducing appreciable DNA damage. These results indicate that, during vertebrate evolution, GNL3L retained the role of the ancestral gene in ribosome biosynthesis, whereas the paralogous nucleostemin acquired a novel genome-protective function. Our results provide a coherent explanation for what had seemed to be contradictory findings about the functions of the invertebrate versus vertebrate genes and are suggestive of how the nucleolus was fine-tuned for a role in genome protection and cell-cycle control as the vertebrates evolved., (© 2014. Published by The Company of Biologists Ltd.)