Investigative biological therapies for primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease characterized by dryness of the eyes and mouth. The histological feature is mononuclear cell infiltration in exocrine glands, primarily salivary and lachrymal glands. As the disease progresses, some other tissues and organs may be involved and extraglandular manifestations ensue. The major current treatments are palliative and empirical, and in most cases the outcomes are not satisfactory. Emerging data indicate a critical role of lymphocytes in its development and progression. While pioneering work targeting B cells has demonstrated some encouraging results, more trials are warranted to validate the safety and efficacy. In addition, modulation of T cell function with abatacept ameliorates the severity of pSS. Furthermore, clinical trials to inhibit important cytokines involved in its formation have been carried out. In this article, we summarize and compare current biological therapies in order to find new and effective treatments for pSS.

An optimized culture system for efficient derivation of porcine expanded potential stem cells from preimplantation embryos and by reprogramming somatic cells.

Pigs share anatomical and physiological traits with humans and can serve as a large-animal model for translational medicine. Bona fide porcine pluripotent stem cells (PSCs) could facilitate testing cell and drug therapies. Agriculture and biotechnology may benefit from the ability to produce immune cells for studying animal infectious diseases and to readily edit the porcine genome in stem cells. Isolating porcine PSCs from preimplantation embryos has been intensively attempted over the past decades. We previously reported the derivation of expanded potential stem cells (EPSCs) from preimplantation embryos and by reprogramming somatic cells of multiple mammalian species, including pigs. Porcine EPSCs (pEPSCs) self-renew indefinitely, differentiate into embryonic and extra-embryonic lineages, and permit precision genome editing. Here we present a highly reproducible experimental procedure and data of an optimized and robust porcine EPSC culture system and its use in deriving new pEPSC lines from preimplantation embryos and reprogrammed somatic cells. No particular expertise is required for the protocols, which take ~4-6 weeks to complete. Importantly, we successfully established pEPSC lines from both in vitro fertilized and somatic cell nuclear transfer-derived embryos. These new pEPSC lines proliferated robustly over long-term passaging and were amenable to both simple indels and precision genome editing, with up to 100% targeting efficiency. The pEPSCs differentiated into embryonic cell lineages in vitro and teratomas in vivo, and into porcine trophoblast stem cells in human trophoblast stem cell medium. We show here that pEPSCs have unique epigenetic features, particularly H3K27me3 levels substantially lower than fibroblasts.

Human and Pig Pluripotent Stem Cells: From Cellular Products to Organogenesis and Beyond.

Pluripotent stem cells (PSCs) are important for studying development and hold great promise in regenerative medicine due to their ability to differentiate into various cell types. In this review, we comprehensively discuss the potential applications of both human and pig PSCs and provide an overview of the current progress and challenges in this field. In addition to exploring the therapeutic uses of PSC-derived cellular products, we also shed light on their significance in the study of interspecies chimeras, which has led to the creation of transplantable human or humanized pig organs. Moreover, we emphasize the importance of pig PSCs as an ideal cell source for genetic engineering, facilitating the development of genetically modified pigs for pig-to-human xenotransplantation. Despite the achievements that have been made, further investigations and refinement of PSC technologies are necessary to unlock their full potential in regenerative medicine and effectively address critical healthcare challenges.

Human early syncytiotrophoblasts are highly susceptible to SARS-CoV-2 infection.

Direct in vivo investigation of human placenta trophoblast's susceptibility to SARS-CoV-2 is challenging. Here we report that human trophoblast stem cells (hTSCs) and their derivatives are susceptible to SARS-CoV-2 infection, which reveals heterogeneity in hTSC cultures. Early syncytiotrophoblasts (eSTBs) generated from hTSCs have enriched transcriptomic features of peri-implantation trophoblasts, express high levels of angiotensin-converting enzyme 2 (ACE2), and are productively infected by SARS-CoV-2 and its Delta and Omicron variants to produce virions. Antiviral drugs suppress SARS-CoV-2 replication in eSTBs and antagonize the virus-induced blockage of STB maturation. Although less susceptible to SARS-CoV-2 infection, trophoblast organoids originating from hTSCs show detectable viral replication reminiscent of the uncommon placental infection. These findings implicate possible risk of COVID-19 infection in peri-implantation embryos, which may go unnoticed. Stem cell-derived human trophoblasts such as eSTBs can potentially provide unlimited amounts of normal and genome-edited cells and facilitate coronavirus research and antiviral discovery.

Folate Supplementation for Methotrexate Therapy in Patients With Rheumatoid Arthritis: A Systematic Review.

OBJECTIVE: To review the evidence for benefits and harms of folate (folic acid or folinic acid) supplementation on methotrexate (MTX) treatment for rheumatoid arthritis (RA), to assess whether or not folate supplementation would reduce MTX toxicity or reduce MTX benefits, and to decide whether a higher MTX dosage is essential. METHODS: We performed a sensitive search strategy and searched systematically the Medline, Embase, Web of Science and Cochrane Library databases from inception to 2 June 2016. Abstracts from major rheumatology meetings and major trial registers were also searched to retrieve all randomized controlled trials that interested us. RESULTS: Seven studies with 709 patients were included. No significant heterogeneity was found between these trials. For RA patients treated with MTX, those supplied with folate were less likely to have elevated transaminase (odds ratio [OR] 0.15; 95% confidence interval [95% CI] 0.10, 0.23 [p < 0.00001]) and gastrointestinal side-effects such as nausea and vomiting (OR 0.71; 95% CI 0.51, 0.99 [p = 0.04]). Folate appeared to promote compliance to MTX as it reduced patient withdrawal compared to placebo (OR 0.29; 95% CI 0.21, 0.42 [p < 0.00001]). There was no statistical difference for mouth sores between folate and placebo (OR 0.83; 95% CI 0.57, 1.22 [p = 0.35]). As the markers of disease activity in those trials were not consistent, it was impossible to decide whether folate supplementation reduced MTX efficacy. Besides, we compared high-dose folate (≥25 mg per week) and low-dose folate (≤10 mg per week) on MTX efficacy, finding no statistical difference (OR 2.07; 95% CI 0.81, 5.30 [p = 0.13]), nor on MTX toxicity (OR 1.56; 95% CI 0.80,3.04 [p = 0.19]). CONCLUSION: Folate supplementation can reduce the incidence of hepatotoxicity and gastrointestinal side-effects of MTX in patients with RA. It can also reduce patient withdrawal from MTX treatment. Although it tended to reduce mouth sores, it had no statistical significance. No significant difference was found between high-dose folate and low-dose folate on MTX efficacy or toxicity.

Successful treatment for acute prosthetic joint infection due to MRSA and Candida albicans: a case report and literature review.

Methicillin-resistant Staphylococcus aureus (MRSA) and Candidal prosthetic joint infections (PJIs) are very rare, and the optimal management for these patients is still unknown. A 54-year-old man with traumatic arthritis due to previous electric injury successfully retained the implant despite the successive infection with MRSA and Candida albicans after total knee arthroplasty (TKA). Continuous lavage with vancomycin was used to control MRSA infection and repeated local washout plus oral swallow with voriconazole tablet were administered to eradicate C. albicans. Additional three reported cases were identified by the criteria of selecting patients with concomitant and/or successive MRSA and Candidal PJIs. Different methods were applied with variable outcomes. Therefore, several risk factors such as intra-articular corticosteroid injection, high frequency of door openings in the operating room, excessive blood loss and allogeneic red blood cell transfusions should be avoided. Debridement, antibiotics and implant retention (DAIR) can be an alternative in dedicated patients to control acute MRSA and Candidal PJIs. Particularly, repeated intra-articular washout with susceptible drugs and a prolonged duration of oral antibiotics was essential for microbial control.

ANCA positive relapsing polychondritis, Graves disease, and suspected moyamoya disease: A case report.

RATIOINALE: Relapsing polychondritis (RP) is a rare and heterogeneous disease complex of unknown origin which basically affects cartilaginous structures, 40% of which accompanied by rheumatic, hematologic, and endocrine disease. Among them, vasculitis is the most common accompanying type and usually presented with positive antineutrophilic cytoplasmic antibody (ANCA). The presence of ANCA could be primary or drug-induced like propylthiouracil (PTU). Central involvement of RP is very rare, and there is almost no report of cerebral vasculopathy manifested as moyamoya. PATIENT CONCERNS: A 26-year-old woman complained about recurrent fever, auricular chondritis, ocular inflammation, and arthritis. She had an 8-year drug intake of PTU for Graves disease. Myeloperoxidase antineutrophilc cytoplasmic antibodies (MPO-ANCA) were found positive. Magnetic resonance angiography (MRA) detected multiple intracranial vasculopathy which we highly suspected it as moyamoya disease. DIAGNOSES: Relapsing polychondritis, Graves disease and suspected moyamoya disease were clinically diagnosed. INTERVENTIONS AND OUTCOMES: In case of possible PTU-induced vasculitis and the aggravation of vasculopathy, PTU was replaced by Iodine-131 (I) therapy. Induction treatment included oral prednisone 30 mg daily and oral cyclophosphamide 100 mg daily. Symptoms rapidly relieved before discharge. Inflammation markers were normal and MPO-ANCA decreased in 3 weeks after admission. Prednisone was gradually tapered to 7.5 mg daily and at month 10 azathioprine was continued for maintenance. LESSONS: RP can overlap with Graves disease and moyamoya disease; comprehensive tests should be performed when admission. When relapsing polychondritis is accompanied with Graves disease, especially when ANCA is positive, PTU should be avoided.