Current state of research on exercise for the treatment of myasthenia gravis: A scoping review.

OBJECTIVE: To provide a comprehensive overview of existing evidence, research gaps, and future research priorities concerning the treatment of myasthenia gravis (MG) using exercise therapies. METHOD: Clinical studies on exercise treatment for MG were searched in nine databases to conduct a scoping review. Two independent researchers screened the literature and comprehensively analyzed the characteristics and limitations of the included articles. RESULTS: A total of 5725 studies were retrieved, of which 24 were included. The included studies were conducted in 16 different countries/regions and 456 patients were enrolled. Study designs included both interventional and observational studies. Exercise interventions included aerobic exercise, resistance exercise, balance training, and stretch training, and are typically administered in conjunction with medication, usual care, or some other interventions. The intensity, frequency, and duration of exercise interventions varied hugely among studies. Six-minute walk test, adverse events, muscle strength, MG quality of life-15 scale, forced vital capacity, quantitative MG scale, and MG activities of daily living scale were the most frequently used outcomes. All studies reported results in favor of the efficacy and safety of exercise in MG, and exercise-related adverse events were reported in two studies. CONCLUSION: This scoping review provides an overview of the evidence concerning exercise treatment for MG. Key gaps in evidence include a limited number of participants, complex interventions, variability in outcome selection, and insufficient reporting in publications. The promotion of exercise treatment for MG still encounters several obstacles. A larger population, rigorous study design and conduction, standardized interventions and outcomes, and standardized reporting are essential.

Photoinduced deformation behavior of poly(aryl ether)s with different azobenzene groups in the side chain.

Azobenzene-containing poly(aryl ether)s are a potential type of photoinduced deformable high-performance polymer. However, research on photoinduced deformation of azobenzene-containing poly(aryl ether)s focuses mainly on poly(aryl ether)s containing azobenzene groups in the main chain. In this paper, the photoinduced deformation of poly(aryl ether)s containing azobenzene groups in the side chain was studied for the first time. Two novel poly(aryl ether)s containing azobenzene groups in the side chain were synthesized, and their photoinduced isomerization behavior and photoinduced deformation behavior were studied. It could be seen that the match of the excitation luminescence to the maximum absorption peak of the azobenzene groups was more compatible, and the photoinduced motion of the polymers was faster. In addition, poly(aryl ether)s containing azobenzene groups in the side chain showed highly stable photoinduced deformation. The results of this work will be helpful for designing polymers which could be controlled by lasers of different wavelengths.

Characteristics of corneal microcysts in Hong Kong children wearing orthokeratology.

PURPOSE: To report the characteristics (prevalence, severity, and location) of corneal epithelial microcysts and investigate associated risk factors in children wearing orthokeratology (ortho-k) lenses. METHOD: Ninety-five myopic children wearing ortho-k lenses (examined by one of three independent investigators from March to September 2020) were included in this retrospective cross-sectional study. Pertinent data at baseline before ortho-k treatment and at the aftercare visits (the first visit when the microcysts were observed for children with microcysts, and the last visit before October 2020 for children without microcysts) were retrieved and analysed. RESULTS: A microcystic response was observed in 52.6% of children wearing ortho-k lenses. Children with high myopia (≥ 5.00 D) had a higher prevalence (100.0%, 23/23) and severity (69.5% (16/23) > grade 2 Efron scale) compared to children with low myopia (≤ 4.00 D) (prevalence of 37.5% (27/72) and 7.0% (5/72) > grade 2, p < 0.001). Microcysts were predominantly (86.0%) observed in the region of the inferior pigmented arc, typically originating in the inferior mid-peripheral cornea, and expanding over time into a semi- or whole annulus. Baseline myopia and topographical change at the treatment zone centre were significantly greater (p < 0.05) in low myopic children with microcysts (univariate analyses). CONCLUSIONS: During the COVID-19 pandemic, probably due to lifestyle changes, microcysts were frequently observed in children wearing ortho-k lenses and were associated with higher baseline myopia. Practitioners should examine ortho-k wearers with caution using a slit lamp with high magnification and illumination, especially the mid-peripheral cornea. The use of highly oxygen permeable lenses and frequent aftercare are necessary for ortho-k wearers, especially those with higher myopia.

TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential.

Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC "eraser" by mRNA oxidation, abolishes YBX1-HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors.

Salvage lenvatinib/everolimus combination therapy after immune checkpoint inhibitor and VEGFR tyrosine kinase inhibitor for metastatic renal cell carcinoma.

Background: The optimal treatment for metastatic renal cell carcinoma (mRCC) patients who have progressed after both immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) remains uncertain. Lenvatinib and everolimus (LE) are frequently used in combination as salvage therapy because of their different antitumor mechanisms, but efficacy and toxicity data in this setting are lacking. Methods: We retrospectively reviewed charts from two academic centers for 71 adult mRCC patients who received LE after prior ICI and TKI exposure. We evaluated patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details. Outcomes of interest included objective response rate (ORR), time to treatment failure (TTF), overall survival (OS), ≥grade 3 toxicities, and schedule or dosage changes, which were evaluated using descriptive statistics, chi-square test, Cox proportional hazards model, and the Kaplan-Meier method. Results: The median age was 64 (range 31-84). Most patients had clear cell histology (84.5%) and had undergone nephrectomy (80.3%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). The average ORR was 26.8%, while the median TTF was 5.5 months (95% confidence interval [CI], 3.5-7.6) and the median OS was 9 months (95% CI, 7.6-12.9). Intermediate and poor IMDC risks were independently associated with a significantly worse TTF compared to favorable risk (hazard ratio (HR), 3.03, 95% CI, 1.18-7.79), as was ≥4L treatment vs. 2L/3L treatment (HR, 2.02, 95% CI, 1.08-3.8). Of the 71 patients, 57.7% had ≥grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance. Conclusions: LE therapy is feasible but has modest efficacies following ICI/TKI treatment. Patients with favorable risk or treated earlier may have a better treatment response. These observations need to be confirmed in prospective studies.

ALDH1A1 promotes PARP inhibitor resistance by enhancing retinoic acid receptor-mediated DNA polymerase θ expression.

Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi) have been approved for both frontline and recurrent setting in ovarian cancer with homologous recombination (HR) repair deficiency. However, more than 40% of BRCA1/2-mutated ovarian cancer lack the initial response to PARPi treatment, and the majority of those that initially respond eventually develop resistance. Our previous study has demonstrated that increased expression of aldehyde dehydrogenase 1A1 (ALDH1A1) contributes to PARPi resistance in BRCA2-mutated ovarian cancer cells by enhancing microhomology-mediated end joining (MMEJ) but the mechanism remains unknown. Here, we find that ALDH1A1 enhances the expression of DNA polymerase θ (Polθ, encoded by the POLQ gene) in ovarian cancer cells. Furthermore, we demonstrate that the retinoic acid (RA) pathway is involved in the transcription activation of the POLQ gene. The RA receptor (RAR) can bind to the retinoic acid response element (RARE) located in the promoter of the POLQ gene, promoting transcription activation-related histone modification in the presence of RA. Given that ALDH1A1 catalyzes the biosynthesis of RA, we conclude that ALDH1A1 promotes POLQ expression via the activation of the RA signaling pathway. Finally, using a clinically-relevant patient-derived organoid (PDO) model, we find that ALDH1A1 inhibition by the pharmacological inhibitor NCT-505 in combination with the PARP inhibitor olaparib synergistically reduce the cell viability of PDOs carrying BRCA1/2 mutation and positive ALDH1A1 expression. In summary, our study elucidates a new mechanism contributing to PARPi resistance in HR-deficient ovarian cancer and shows the therapeutic potential of combining PARPi and ALDH1A1 inhibition in treating these patients.

A sulfated polysaccharide from Dictyosphaeria cavernosa: Structural characterization and effect on immunosuppressive recovery.

A homogeneous sulfated polysaccharide DCS1 was obtained from Dictyosphaeria cavernosa by alkali extraction and chromatography purification. On the basis of chemical and spectroscopic analyses, DCS1 was a novel mannan-type sulfated polysaccharide and had a molecular weight of 15.48 kDa. DCS1 consisted of a main chain of (1 â†’ 4)-α-d-Manp units with partial sulfate substitution at C-2 and branches at C-2/C-6. DCS1 possessed a potent immune-enhancing effect in vitro evaluated by the assays of lymphocytes proliferation and macrophage phagocytosis. The immunomodulatory effect of DCS1 in vivo was further investigated using immunosuppressed mice induced by cyclophosphamide (Cy). The data showed that DCS1 markedly increased the spleen and thymus indexes, and ameliorated the Cy-induced damage to spleen and thymus. Moreover, DCS1 had a significant effect on hematopoietic function recovery, and promoted the secretion of the interleukin-2 and tumor necrosis factor-α. Notably, DCS1 reversed the reduction of CD4+ T cells, improved the disorder of CD4+/CD8+ T cells and enhanced the immune response. The investigation demonstrated that the sulfated polysaccharide DCS1 with novel structure could be a hopeful immunomodulatory agent.

Molecular Mechanism of Ferroptosis in Orthopedic Diseases.

Ferroptosis is a new iron-dependent programmed cell death process that is directly mediated by the accumulation of lipid peroxides and reactive oxygen species. Numerous studies have shown that ferroptosis is important in regulating the occurrence and development of bone-related diseases, but the underlying mechanisms are not completely clear. Herein, we review the progress of the mechanism of ferroptosis in bone marrow injury, osteoporosis, osteoarthritis, and osteosarcoma and attempt to deeply understand the regulatory targets of ferroptosis, which will open up a new way for the prevention and treatment of orthopedic diseases.

Blood flow restriction training promotes functional recovery of knee joint in patients after arthroscopic partial meniscectomy: A randomized clinical trial.

Purpose: To explore the effect of blood flow restriction training (BFRT) on the recovery of knee function in patients after arthroscopic partial meniscectomy (APM). Methods: Forty patients undergoing APM surgery were included in this parallel group, two-arm, single-assessor blinded, randomized clinical trial. The subjects were randomly divided into two groups: routine rehabilitation group (RR Group, n = 20) and routine rehabilitation + blood flow restriction training group (RR + BFRT Group, n = 20). One subject in each group dropped out during the experiment. All patients received 8 weeks of routine rehabilitation starting from the second day after APM. In addition, patients in the RR + BFRT group required additional BFRT twice a week. Visual analogue scale (VAS) score, range of motion (ROM), one-leg standing test (OLST) score, Lysholm knee score, quadriceps muscle strength, quadriceps thickness, and thigh circumference were evaluated at preoperative, postoperative, 4 and 8 weeks after surgery. SPSS 25.0 software was used for statistical analysis of the data. Repeated measures ANOVA was used if the data were normally distributed and had homogeneity of variance. Generalized estimating equations were chosen if the data were not normally distributed or had homogeneity of variance. Results: There were no significant differences in VAS score, ROM, OLST score, Lysholm knee score, quadriceps muscle strength, quadriceps thickness, and thigh circumference between the two groups before surgery (p > 0.05). Compared with postoperative, VAS score, ROM, OLST score, Lysholm knee score, and thigh circumference were significantly improved in the RR group (p < 0.05), while quadriceps muscle strength and quadriceps thickness were not significantly enhanced at 8 weeks postoperatively (p > 0.05). However, VAS score, ROM, OLST score, Lysholm knee score, quadriceps muscle strength, quadriceps thickness, and thigh circumference were all significantly improved in the RR + BFRT group at 8 weeks postoperatively (p < 0.05). Furthermore, compared with the RR group, VAS score (50% vs. 86%), ROM (7.9% vs. 16.0%), OLST score (57.3% vs. 130.1%), Lysholm knee score (38.4% vs. 55.7%), relative peak torque (11.0% vs. 84.7%), mean power (20.6% vs. 88.1%), rectus femoris thickness (0.40% vs. 13.0%), vastus medialis (0.29% vs. 5.32%), vastus lateralis (0% vs. 6.2%), vastus internus (0% vs. 5.8%), and thigh circumference (2.7% vs. 5.8%) in the RR + BFRT group were significantly improved at 4 and 8 weeks postoperatively (p < 0.05). Conclusion: BFRT combined with routine rehabilitation training can better promote the recovery of knee joint function in patients after APM, especially the improvement of quadriceps muscle strength and thickness.

Mitophagy-A New Target of Bone Disease.

Bone diseases are usually caused by abnormal metabolism and death of cells in bones, including osteoblasts, osteoclasts, osteocytes, chondrocytes, and bone marrow mesenchymal stem cells. Mitochondrial dysfunction, as an important cause of abnormal cell metabolism, is widely involved in the occurrence and progression of multiple bone diseases, including osteoarthritis, intervertebral disc degeneration, osteoporosis, and osteosarcoma. As selective mitochondrial autophagy for damaged or dysfunctional mitochondria, mitophagy is closely related to mitochondrial quality control and homeostasis. Accumulating evidence suggests that mitophagy plays an important regulatory role in bone disease, indicating that regulating the level of mitophagy may be a new strategy for bone-related diseases. Therefore, by reviewing the relevant literature in recent years, this paper reviews the potential mechanism of mitophagy in bone-related diseases, including osteoarthritis, intervertebral disc degeneration, osteoporosis, and osteosarcoma, to provide a theoretical basis for the related research of mitophagy in bone diseases.

Effects of Photobiomodulation and Low-Intensity Stretching on Delayed-Onset Muscle Soreness: A Randomized Control Trial.

Objective: This study aimed to investigate the effects of photobiomodulation (PBM), low-intensity stretching, and their combination on delayed-onset muscle soreness (DOMS) in the untrained population. The relationships between DOMS and muscle function and functional performance were also tested. Methods: Fifty-four participants were randomized into four groups. Eccentric exercise was used to induce DOMS. Each group received either no treatment, PBM, stretching or PBM combined with stretching at 24, 48, and 72 h postexercise. Pressure pain threshold (PPT), numerical rating scale (NRS), single-leg forward jump (SLFJ), and maximum isometric voluntary contraction (MIVC) were measured at baseline, 24, 48, 72, and 96 h after eccentric exercise. Between-group differences were tested using two-way repeated measures analysis of variance and the relationships between DOMS and MIVC, and SLFJ were examined using Pearson's correlation analysis. Results: The PPT at the vastus medialis and vastus lateral in the PBM combined with stretching group was significantly lower than that in control group at 72 h (p = 0.045) and 48 h (p = 0.037) postexercise. No significant between-group difference in PPT was found for the rest occasions. There was no significant between-group difference in NRS, MVIC, and SLFJ on any occasion (p ≥ 0.052). DOMS was not correlated with MIVC and SLFJ (p ≥ 0.09). Conclusions: PBM or low-intensity stretching did not affect DOMS and functional performance in untrained individuals. The combination of PBM and low-intensity stretching increased pain sensitivity and did not relieve soreness. The DOMS was not associated with either muscle function or functional performance.

Sarcopenia Was a Poor Prognostic Predictor for Patients With Advanced Lung Cancer Treated With Immune Checkpoint Inhibitors.

Background: It remains not well known whether skeletal muscle mass (SMM) loss has any impact on the effectiveness of immune checkpoint inhibitors (ICIs) in patients with advanced lung cancer. We aimed to evaluate the association between SMM and clinical outcome of patients with advanced lung cancer receiving ICIs as first line or second line. Materials and Methods: From March 1st, 2019 to March 31st, 2021 at our hospital, 34 patients with advanced lung cancer treated with first-line or second-line ICIs were enrolled retrospectively. The estimation of skeletal muscle index (SMI) for sarcopenia was assessed at the level of the third lumbar vertebra (L3) on computed tomography (CT) images obtained within 4 weeks before initiation of ICIs treatment. The impact of sarcopenia (low SMI) on progression free survival (PFS) was analyzed using Kaplan-Meier method and log-rank tests. The effect of various variables on PFS was evaluated using Cox proportional hazards regression model with univariate and multivariate analysis. The impact on treatment response including objective response rate (ORR) and disease control rate (DCR) and immunotherapy related adverse events (irAEs) between patients with and without sarcopenia was compared by the chi-squared test. The comparison of SMI value between patients with objective response (OR), disease control (DC) and those without OR and DC was used student t-test or Mann-Whitney U test. Results: Both in univariate and multivariate analysis, sarcopenia and treatment lines were the predictive factors for PFS (p < 0.05). Patients with sarcopenia had significantly shorter PFS than that of non-sarcopenic ones [6.57 vs. 16.2 months, hazard ratios (HR) = 2.947 and 3.542, and 95% confidence interval (CI): 1.123-13.183 and 1.11-11.308, p = 0.022 and 0.033]. No significant difference in ORR and irAEs was found. Patients with sarcopenia had lower DCR than those without sarcopenia. The mean SMI value of DCR group and non-DCR group was 32.94 ± 5.49 and 44.77 ± 9.06 cm2/m2, respectively (p = 0.008). Conclusion: Sarcopenia before immunotherapy might be a significant predictor for poor prognosis including shorter PFS and lower DCR in patients with advanced lung cancer treated with ICIs as first line or second line.

Immunomodulatory Activity In Vitro and In Vivo of a Sulfated Polysaccharide with Novel Structure from the Green Alga Ulvaconglobata Kjellman.

Algae accumulate large amounts of polysaccharides in their cell walls or intercellular regions. Polysaccharides from algae possess high potential as promising candidates for marine drug development. In this study, a sulfated polysaccharide, UCP, from the green alga Ulva conglobata Kjellman was obtained by water extraction, anion-exchange, and size-exclusion chromatography purification, and its structure was characterized by a combination of chemical and spectroscopic methods. UCP mainly consisted of →4)-α/ß-l-Rhap-(1→, →4)-ß-d-Xylp-(1→ and →4)-ß-d-GlcAp-(1→ residues. Sulfate ester groups were substituted mainly at C-3 of →4)-l-Rhap-(1→ and C-2 of →4)-ß-d-Xylp-(1→. Partial glycosylation was at C-2 of →4)-α-l-Rhap-(1→ residues. UCP possessed a potent immunomodulatory effect in vitro, evaluated by the assays of lymphocyte proliferation and macrophage phagocytosis. The immunomodulatory activity of UCP in vivo was further investigated using immunosuppressive mice induced by cyclophosphamide. The results showed that UCP markedly increased the spleen and thymus indexes and ameliorated the cyclophosphamide-induced damage to the spleen and thymus. UCP could increase the levels of white blood cells, lymphocytes, and platelets, and improve the hematopoietic inhibition caused by cyclophosphamide. Moreover, UCP significantly promoted the secretions of the immunoglobulin (Ig)G, IgE, and IgM. The data demonstrated that UCP is a novel sulfated polysaccharide and may be a promising immunomodulatory agent.

Antidiabetic-activity sulfated polysaccharide from Chaetomorpha linum: Characteristics of its structure and effects on oxidative stress and mitochondrial function.

A water-soluble polysaccharide from the green alga Chaetomorpha linum, designated CHS2, was obtained by water extraction, preparative anion-exchange and size-exclusion chromatography. Results of chemical and spectroscopic analyses showed that CHS2 was a sulfated rhamnogalactoarabinan, and its backbone was mainly constituted by 4-linked and 3,4-linked ß-l-arabinopyranose with sulfate groups at C-2/C-3 of 4-linked ß-l-arabinopyranose. The branching contained 4-linked, 6-linked ß-d-galactopyranose and terminal rhamnose residues. Based on the inhibition of human islet amyloid polypeptide (hIAPP) aggregation and morphology change of hIAPP aggregates in in vitro tests, it was proved that CHS2 effectively inhibited the hIAPP aggregation and possessed strong antidiabetic activity. CHS2 was nearly no toxicity in NIT-1 cells and could attenuate hIAPP-induced cytotoxicity. CHS2 may significantly reduce the generation of intracellular reactive oxygen species and hIAPP aggregation-induced oxidative stress in NIT-1 cells. CHS2 was co-localized with mitochondria, and largely protected mitochondria function from hIAPP aggregation-induced damage through stabilizing mitochondrial membrane potential and enhancing the mitochondrial complex I, II or III activity and ATP level. The data demonstrated that CHS2 could have potential prospect to become an antidiabetic drug for type 2 diabetes mellitus treatment.

TET2 Suppresses VHL Deficiency-Driven Clear Cell Renal Cell Carcinoma by Inhibiting HIF Signaling.

Inactivating mutations of von Hippel-Lindau (VHL) are highly prevalent in clear cell renal cell carcinoma (ccRCC). Improved understanding of the vulnerabilities of VHL-deficient ccRCC could lead to improved treatment strategies. The activity of DNA dioxygenase ten-eleven translocation (TET)2 is significantly reduced in multiple cancers by different mechanisms, but its role in ccRCC progression remains unclear. Here, we report that increased expression of TET2, but not TET1 and TET3, is negatively associated with tumor metastasis and advanced tumor stage and is positively associated with good prognosis uniquely in ccRCC among all 33 types of cancer in The Cancer Genome Atlas datasets. TET2 restrained glycolysis and pentose phosphate pathway metabolism in a VHL deficiency-dependent manner, thereby suppressing ccRCC progression. Notably, TET2 and VHL mutations tended to cooccur in ccRCC, providing genetic evidence that they cooperate to inhibit the progression of ccRCC. Mechanistically, TET2 was recruited by transcription factor HNF4α to activate FBP1 expression, which antagonized the function of hypoxia-inducible factor-1/2α (HIF1/2α) in metabolic reprogramming to impede ccRCC growth. Stimulating the TET2-FBP1 axis with vitamin C repressed the growth of VHL-deficient ccRCC with wild-type TET2 and increased the sensitivity to glycolysis inhibitors. Moreover, combined expression levels of the HNF4α-TET2-FBP1 axis served as a biomarker of prognosis in patients with ccRCC. This study reveals a unique function of TET2 in the suppression of tumor metabolism and HIF signaling, and it also provides therapeutic targets, potential drugs, and prognostic markers for the management of ccRCC. SIGNIFICANCE: The identification of TET2-mediated inhibition of HIF signaling and tumor metabolic reprogramming provides insights for new therapeutic strategies for VHL-deficient ccRCC.

D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1.

Breast cancer is the most frequent malignancy in women worldwide, and triple-negative breast cancer (TNBC) patients have the worst prognosis and highest risk of recurrence. The therapeutic strategies for TNBC are limited. It is urgent to develop new methods to enhance the efficacy of TNBC treatment. Previous studies demonstrated that D-mannose, a hexose, can enhance chemotherapy in cancer and suppress the immunopathology of autoimmune diseases. Here, we show that D-mannose can significantly facilitate TNBC treatment via degradation of PD-L1. Specifically, D-mannose can activate AMP-activated protein kinase (AMPK) to phosphorylate PD-L1 at S195, which leads to abnormal glycosylation and proteasomal degradation of PD-L1. D-mannose-mediated PD-L1 degradation promotes T cell activation and T cell killing of tumor cells. The combination of D-mannose and PD-1 blockade therapy dramatically inhibits TNBC growth and extends the lifespan of tumor-bearing mice. Moreover, D-mannose-induced PD-L1 degradation also results in messenger RNA destabilization of DNA damage repair-related genes, thereby sensitizing breast cancer cells to ionizing radiation (IR) treatment and facilitating radiotherapy of TNBC in mice. Of note, the effective level of D-mannose can be easily achieved by oral administration in mice. Our study unveils a mechanism by which D-mannose targets PD-L1 for degradation and provides methods to facilitate immunotherapy and radiotherapy in TNBC. This function of D-mannose may be useful for clinical treatment of TNBC.

Anti-diabetic activity of a sulfated galactoarabinan with unique structural characteristics from Cladophora oligoclada (Chlorophyta).

The polysaccharide from green alga Cladophora oligoclada, OHSS2, was a sulfated galactoarabinan which was constituted by a backbone of (1 â†’ 4)-ß-l-arabinopyranose units with partial sulfate at C-3 of (1 â†’ 4)-ß-l-arabinopyranose units. The side chains containing (1 â†’ 4)-ß-l-arabinopyranose, (1 â†’ 4)-ß-d-galactopyranose and/or (1 â†’ 4,6)-ß-d-galactopyranose units were in C-2/C-3 of (1 â†’ 4)-ß-l-arabinopyranose units. OHSS2 had strong anti-diabetic activity in vitro assessed by inhibition of human islet amyloid polypeptide (hIAPP) aggregation. The mechanism analysis of anti-diabetic activity showed that OHSS2 diminished the production of intracellular reactive oxygen species and alleviated hIAPP aggregation-induced oxidative stress in NIT-1 cells. OHSS2 stabilized mitochondrial membrane potential, and enhanced the mitochondrial complex I, II or III activity and ATP level. Thus, OHSS2 effectively protected mitochondria from hIAPP aggregation-induced damage. Furthermore, OHSS2 was co-localized with mitochondria and could have a direct influence on mitochondrial function. These results revealed that OHSS2 had potential as a novel anti-diabetic agent.

Structural Characterization, Antioxidant and Antitumor Activities of the Two Novel Exopolysaccharides Produced by Debaryomyces hansenii DH-1.

Exopolysaccharides produced by edible microorganisms exhibit excellent constructive physicochemical and significant biological activity, which provide advantages for the food or pharmaceutical industries. Two novel exopolysaccharides produced by Debaryomyces hansenii DH-1 were characterized, named S1 and S2, respectively. S1, with a molecular weight of 34.594 kDa, primarily consisted of mannose and glucose in a molar ratio of 12.19:1.00, which contained a backbone fragment of α-D-Manp-(1→4)-α-D-Manp-(1→2)-α-D-Glcp-(1→3)-α-D-Manp-(1→3)-ß-D-Glcp-(1→4)-ß-D-Manp-(1→. S2, with a molecular weight of 24.657 kDa, was mainly composed of mannose and galactose in a molar ratio of 4.00:1.00, which had a backbone fragment of α-D-Manp-(1→6)-ß-D-Manp-(1→2)-α-D-Manp-(1→4)-α-D-Galp-(1→3)-ß-D-Manp-(1→6)-α-D-Manp-(1→. Both S1 and S2 exhibited good thermal stability and potent hydroxyl radical scavenging activity, with ~98%. Moreover, S1 possessed an additional strong iron-reducing capacity. In vitro antitumor assays showed that S1 and S2 significantly inhibited the proliferation of Hela, HepG2, and PC-9 cancer cells. Moreover, PC-9 was more sensitive to S1 compared with S2. The above results indicate that S1 and S2 have great potential to be utilized as natural antioxidants and candidates for cancer treatment in the food and pharmaceutical industries.

The safety of COVID-19 vaccines in patients with myasthenia gravis: A scoping review.

Background: COVID-19 vaccines are required for individuals with myasthenia gravis (MG), as these patients are more likely to experience severe pneumonia, myasthenia crises, and higher mortality rate. However, direct data on the safety of COVID-19 vaccines in patients with MG are lacking, which results in hesitation in vaccination. This scoping was conducted to collect and summarize the existing evidence on this issue. Methods: PubMed, Cochrane Library, and Web of Science were searched for studies using inclusion and exclusion criteria. Article titles, authors, study designs, demographics of patients, vaccination information, adverse events (AEs), significant findings, and conclusions of included studies were recorded and summarized. Results: Twenty-nine studies conducted in 16 different countries in 2021 and 2022 were included. Study designs included case report, case series, cohort study, cross-sectional study, survey-based study, chart review, and systemic review. A total of 1347 patients were included. The vaccines used included BNT162b2, mRNA-1273, ChAdOx1 nCoV-19, inactivated vaccines, and recombinant subunit vaccines. Fifteen case studies included 48 patients reported that 23 experienced new-onset, and five patients experienced flare of symptoms. Eleven other types of studies included 1299 patients reported that nine patients experienced new-onset, and 60 participants experienced flare of symptoms. Common AEs included local pain, fatigue, asthenia, cephalalgia, fever, and myalgia. Most patients responded well to treatment without severe sequelae. Evidence gaps include limited strength of study designs, type and dose of vaccines varied, inconsistent window of risk and exacerbation criteria, limited number of participants, and lack of efficacy evaluation. Conclusion: COVID-19 vaccines may cause new-onset or worsening of MG in a small proportion of population. Large-scale, multicenter, prospective, and rigorous studies are required to verify their safety.

AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer.

PURPOSE: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)-a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression. EXPERIMENTAL DESIGN: AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs). RESULTS: AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression (<1,000 molecules per cell). AMG 757 effectively engaged systemically administered human T cells, induced T-cell activation, and redirected T cells to lyse tumor cells to promote significant tumor regression and complete responses in PDX models of SCLC and in orthotopic models of established primary lung SCLC and metastatic liver lesions. AMG 757 was well tolerated with no AMG 757-related adverse findings up to the highest tested dose (4.5 mg/kg weekly) in NHP. AMG 757 exhibits an extended half-life in NHP, which is projected to enable intermittent administration in patients. CONCLUSIONS: AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.