Miracle-dz/UniFAR-FTUs huggingface dataset:
The effect of adjuvants and delivery systems on Th1, Th2, Th17 and Treg cytokine responses in mice immunized with Mycobacterium tuberculosis-specific proteins

Tuberculosis (TB) is a major health problem of global concern. The control of this disease requires appropriate preventive measures, including vaccines. In TB, T helper (Th)1 cytokines provide protection whereas Th2 and T regulatory (Treg) cytokines contribute to the pathogenesis and Th17 cytokines play a role in both protection and pathogenesis. Previous studies with Mycobacterium tuberculosis-specific proteins have identified seven low molecular weight proteins, PE35, ESXA, ESXB, Rv2346c, Rv2347c, Rv3619c, and Rv3620c, as immunodominant antigens inducing Th1-cell responses in humans following natural infection with M. tuberculosis. The aim of this study was to characterize the cytokine responses induced in mice immunized with these proteins, using various adjuvants and delivery systems, i.e. chemical adjuvants (Alum and IFA), non-pathogenic mycobacteria (M. smegmatis and M. vaccae) and a DNA vaccine plasmid (pUMVC6). The immune responses were monitored by quantifying the marker cytokines secreted by Th1 (IFN-ɣ), Th2 (IL-5), Treg (IL-10), and Th17 (IL-17A) cells. DNA corresponding to pe35, esxa, esxb, rv2346c, rv2347c, rv3619c, and rv3620c genes were cloned into the expression vectors pGES-TH-1, pDE22 and pUMVC6 for expression in Escherichia coli, mycobacteria and eukaryotic cells, respectively. Mice were immunized with the recombinants using different adjuvants and delivery systems, and spleen cells were stimulated in vitro with peptides of immunizing proteins to investigate antigen-specific secretion of Th1 (IFN-ɣ), Th2 (IL-5), Treg (IL-10), and Th17 (IL-17A) cytokines. The results showed that spleen cells, from mice immunized with all antigens, secreted the protective Th1 cytokine IFN-ɣ, except ESXB, with one or more adjuvants and delivery systems. However, only Rv3619c consistently induced Th1-biased responses, without the secretion of significant concentrations of Th2, Th17 and Treg cytokines, with all adjuvants and delivery systems. Rv3619c also induced antigen-specific IgG antibodies in immunized mice.
Phase 2 randomized placebo controlled double blind study to assess the efficacy and safety of tecfidera in patients with amyotrophic lateral sclerosis (TEALS Study)

Abstract Background: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder of the human motor system. Neuroinflammation appears to be an important modulator of disease progression in ALS. Specifically, reduction of regulatory T cell (Treg) levels, along with an increase in pro-inflammatory effector T cells, macrophage activation and upregulation of co-stimulatory pathways have all been associated with a rapid disease course in ALS. Autologous infusion of expanded Tregs into sporadic ALS patients, resulted in greater suppressive function, slowing of disease progression and stabilization of respiratory function. Tecfidera (dimethyl fumarate) increases the ratio of anti-inflammatory (Treg) to proinflammatory T-cells in patients with relapsing remitting multiple sclerosis and rebalances the regulatory: inflammatory axis towards a neuroprotective phenotype. Consequently, the aim of this study was to assess the efficacy, safety, and tolerability of Tecfidera in sporadic ALS. Methods: The study is an investigator led Phase 2 multi-center, randomized, placebo controlled, double blind clinical trial assessing the efficacy and safety of Tecfidera in patients with sporadic ALS. The study duration is 40 weeks, with a 36-week study period and end of study visit occurring at 40 weeks or at early termination/withdrawal from study. The TEALS study has been registered with the Australian and New Zealand Clinical Trials registry (ANZCTR) under the trials registration number ACTRN12618000534280 and has been approved by the Human Research Ethics Committee and Research Governance Office at the lead site (Westmead Hospital) with the ethics number HREC/17/WMEAD/353. The participating sites have obtained site specific ethics and governance approvals from the local institution. Results: The primary endpoint is slowing of disease progression as reflected by the differences in the ALS Functional Rating Score-Revised (ALSFRS-R) score at Week 36. The secondary endpoints will include effects in survival, lower motor neuron function, respiratory function, quality of life and safety. Conclusion: This Phase 2 multi-center, randomized, placebo controlled, double blind clinical trial will provide evidence of efficacy and safety of Tecfidera in sporadic ALS.
Renal leukocyte chemotactic factor 2 (ALECT2)-associated amyloidosis in Chinese patients

Abstract Background: Leukocyte chemotactic factor 2 (ALECT2) amyloidosis is one of the recently described types of amyloidosis. In this study, we reported the first large case series of renal ALECT2 amyloidosis in Chinese patients. Methods: We studied the prevalence, clinical characteristics, renal pathology, outcome and genetic features among seven patients diagnosed with renal ALECT2 amyloidosis at Peking University First Hospital of China from 2000 to 2018. Results: Seven patients were diagnosed with ALECT2 amyloidosis, representing 1.9% of the renal biopsy-proven amyloidosis cases. The mean age at diagnosis was 68 years without gender preference. The patients mainly manifested with varying impaired kidney function with a mean estimated glomerular filtration rate of 42.7 mL/min/1.73 m2 (range 8.0–80.5) and proteinuria at 3.9 g/24 h (range 0.4–11.3). There were four ALECT2 amyloidosis patients with concurrent membranous nephropathy (MN), who presented a higher proteinuria (6.4 ± 4.0 g/24 h vs. 2.0 ± 1.8 g/24 h) and higher frequency of nephrotic syndrome (50% vs. 0) than patients with isolated ALECT2 amyloidosis. Renal biopsy showed strongly congophilic amyloid deposits distributed mainly in the renal cortical interstitium, as well as the glomerular mesangium, the inner layer of glomerular basement membrane (GBM), and vascular walls. Two patients with concurrent ALECT2 amyloidosis and MN showed mild amyloid deposits, which have not been identified as ALECT2 amyloidosis by IHC and LMD/MS methods. All patients were corroborated by immunoelectron microscopy to exhibit the specific location of LECT2 in the amyloid fibrils. Genetic analysis revealed no mutations but homozygosity for the G allele encoding valine at position 40 in the mature protein in all patients. Except for one patient who died 8 years later after he was diagnosed with ALECT2 amyloidosis, the others presented with relatively stable renal function during the mean follow-up period of 12.5 months. Conclusions: ALECT2 amyloidosis was the third most common type of renal amyloidosis in Chinese patients from a single centre. The majority of ALECT2 amyloidosis patients were of Han ethnicity, with a high rate of concurrent MN. The recognition and accurate diagnosis of renal ALECT2 amyloidosis should be considered in Chinese patients.
Giant pyoderma gangrenosum in a patient with ulcerative colitis

Abstract Introduction: Pyoderma gangrenosum (PG) is a phenomenon of cutaneous ulceration with unknown etiology. About half the cases have associated extracutaneous manifestations or associated systemic diseases. The most commonly associated systemic disorders include inflammatory bowel disease (IBD), hematologic malignancies, autoimmune arthritis, and vasculitis. This is a case report about giant PG with ulcerative colitis (UC), which is extremely rare. Case Presentation: A 39-year-old female farmer with UC for the past 3 years presented with multiple painful ulcers, erosion, exudation, and crusting on the right leg for 1 month. A cutaneous examination showed diffusely distributed, multiple, well-defined, deep purulent ulcers on the right medial shank measuring 6 to 20 cm and sporadic worm-eaten ulceration on the right ectocnemial, with severe oozing and erosions. The ulcerations exhibited deep undermined borders, granulated tissue and a black eschar at the base. The right shank and feet were severely swollen, restricting movement. The arteria dorsalis pedis pulse was good, with normal sensation on the skin of the right shank and feet. Laboratory examinations showed a white cell count of 11.8 × 109/L, hemoglobin was 91 g/L, erythrocyte sedimentation rate was 82 mm/h, unelevated procalcitonin, serum C-reactive protein was 131.29 mg/L, and a negative tuberculin skin test. Enteroscopy demonstrated endoscopic evidence of UC. A skin lesion biopsy showed superficial erosion and scarring. Partial epidermal hyperplasia, partial epidermal atrophy and thinning, mild edema of the dermal papill. Most of the middle and lower part of the dermis, showed dense lymphocytes, histiocytes, multinucleated giant cells, and neutrophil infiltration. PG with UC was diagnosed based on clinical manifestations, laboratory examinations and enteroscopy results. Interventions: She was treated with topical applications of povidone iodine and kangfuxin solution twice daily, methylprednisolone sodium succinate 40 mg and compound glycyrrhizin 60 mg via intravenous drip once a day, along with thalidomide 50 mg twice daily. The UC was controlled with mesalazine. Outcomes: She required multiple therapies to achieve PG healing 3 months later. No PG recurrence was observed during the 1-year follow-up. Conclusion: Recognizing the clinical features of PG and its pathogenic nature, ensuring timely management fundamental for preventing severe destruction and deformity, and control of associated diseases are important aspects of treatment. Combination therapy is essential for PG patients with IBD.
Aucubin exerts anti-osteoporotic effects by promoting osteoblast differentiation

Osteoporosis is a metabolic disease characterized by reduced osteoblast differentiation and proliferation. Oxidative stress plays a role in the pathogenesis of osteoporosis. Aucubin (AU), an iridoid glycoside, was previously shown to promote osteoblast differentiation. We investigated the effects of AU on MG63 human osteoblast-like cells treated with dexamethasone (Dex) or hydrogen peroxide (H2O2) to induce oxidative damage. AU protected MG63 cells against apoptosis, and promoted increased expression of cytokines associated with osteoblast differentiation, including collagen I, osteocalcin (OCN), osteopontin (OPN), and osterix. In Dex- and H2O2-treated MG63 cells, AU also enhanced the expression of anti-oxidative stress-associated factors in the nuclear respiratory factor 2 signaling pathway, including superoxide dismutases 1 and 2, heme oxygenases 1 and 2, and catalase. In vivo, using a Dex-induced mouse model of osteoporosis, AU promoted increased cortical bone thickness, increased bone density, and tighter trabecular bone. Additionally, it stimulated an increase in the expression of collagen I, OCN, OPN, osterix, and phosphorylated Akt and Smads in bone tissue. Finally, AU stimulated the expression of cytokines associated with osteoblast differentiation in bone tissue and serum. Our data indicate AU may have therapeutic efficacy in osteoporosis.
Keratinocytes-hair follicle bulge stem cells-fibroblasts co-cultures on a tri-layer skin equivalent derived from gelatin/PEG methacrylate nanofibers

Abstract Generation of full thickness skin equivalent models is of increasing interest in tissue engineering because of the limitations inherent to current models. In recent years, considerable interest has been given to electrospun hybrid nanofibers prepared using natural and synthetic combinations of polymers. By blending two polymers, gelatin and PEG methacrylate we created a novel functional hydrogel—named GelMet. By adjusting the concentration of GelMet between 14 and 20wt%, three types of electrospun membranes were fabricated. Keratinocytes, hair follicle bulge stem cells (HFBSCs) and fibroblasts were successfully isolated and cultured in 14 wt%, 17 wt% and 20 wt% GelMet scaffolds respectively and generated a tri-layered electrospun construct. Characterization of GelMet electrospun membranes were compared with those of the pure gelatin nanofibers. Due to plasticity, by incorporating HFBSCs, it is expected to increase the cell content of skin substitute without the need to incorporate several different cell populations. The fiber diameter and pore size of the scaffold for each layer were fabricated in such a way to mimic the structural gradation of collagen matrix across the native skin. Good mechanical properties and dimensional stability of GelMet scaffold, combined with the ability to support cell growth in vitro, suggest its tremendous potential application in skin tissue engineering.
Thymol alleviates AGEs-induced podocyte injury by a pleiotropic effect via NF-κB-mediated by RhoA/ROCK signalling pathway

ABSTRACT Advanced glycation end products (AGE) are those of the most powerful pathogenic factors that related to diabetic complications. In our study, we investigated the beneficial effects of thymol on AGE induced cell injury and apoptosis in human podocytes (HPCs) and attempted to clarify its mechanisms. Our results revealed that stimulation with AGE could significantly activate RhoA/NF-κB pathway. Results showed thymol could markedly suppress inflammatory responses, cell apoptosis and disordered cytoskeleton. Also thymol restored the expression of podocin, restrained migration capacity. Western blot analysis indicated that it could restore the expression of RhoA, ROCK and vimentin, nephrin, podocin and p65 and IκBα phosphorylation. Moreover, si-RhoA also suppressed the expression of pro-inflammatory cytokines, ROCK, and vimentin and the phosphorylation of p65 and IκBα. In conclusion, thymol inhibits AGE-induced cell injury in HPCs by suppressing the RhoA-NF-κB pathway and may be apromising therapeutic agent.
Experience and future perspectives on the use of the Papanicolaou Society of Cytopathology Terminology System for reporting pancreaticobiliary cytology

The Papanicolaou Society of Cytopathology developed a set of guidelines for reporting pancreaticobiliary cytology in 2014 (PB System), with a six‐tiered system: Nondiagnostic, Negative, Atypical, Neoplastic (Benign or Other), Suspicious, and Positive. This proposed scheme incorporates ancillary testing such as biochemical testing of cyst fluids for diagnosis and provides terminology that standardizes the category of the various diseases of the pancreas, some of which are difficult to diagnose specifically by cytology alone. Since its initial publication five and half years ago, several groups have published their experiences on the use of the PB System and have shown that most objectives proposed by the original publication have been achieved. They have shown that there is a better understanding and definition of the diagnostic categories with an associated distribution and risk of malignancy. The diagnostic categories of Neoplastic: Other, Suspicious, and Malignant show a high sensitivity and specificity for the diagnosis of malignancy. The System also provides a multi‐specialist view of pancreatic lesions, with biochemical and radiological findings being incorporated into the final pathological report. The present review summarizes these findings and discusses the future perspectives and foreseen changes that are to be incorporated to a second edition of the reporting System.
Exercise Training Rapidly Increases Hepatic Insulin Extraction in NAFLD

ABSTRACT Purpose We aimed to determine the immediacy of exercise intervention on liver-specific metabolic processes in nonalcoholic fatty liver disease. Methods We undertook a short-term (7-d) exercise training study (60 min·d−1 treadmill walking at 80%–85% of maximal heart rate) in obese adults (N = 13, 58 ± 3 yr, 34.3 ± 1.1 kg·m−2, >5% hepatic lipid by 1H-magnetic resonance spectroscopy). Insulin sensitivity index was estimated by oral glucose tolerance test using the Soonthorpun model. Hepatic insulin extraction (HIE) was calculated as the molar difference in area under the curve (AUC) for insulin and C-peptide (HIE = 1 − (AUCInsulin/AUCC-Pep)). Results The increases in HIE, V˙O2max, and insulin sensitivity index after the intervention were 9.8%, 9.8%, and 34%, respectively (all, P < 0.05). Basal fat oxidation increased (pre: 47 ± 6 mg·min−1 vs post: 65 ± 6 mg·min−1, P < 0.05) and carbohydrate oxidation decreased (pre: 160 ± 20 mg·min−1 vs post: 112 ± 15 mg·min−1, P < 0.05) with exercise training. After the intervention, HIE correlated positively with adiponectin (r = 0.56, P < 0.05) and negatively with TNF-α (r = −0.78, P < 0.001). Conclusions By increasing HIE along with peripheral insulin sensitivity, aerobic exercise training rapidly reverses some of the underlying physiological mechanisms associated with nonalcoholic fatty liver disease, in a weight loss-independent manner. This reversal could potentially act through adipokine-related pathways.
Phenotypic Adaption of Pseudomonas aeruginosa by Hacking Siderophores Produced by Other Microorganisms*

Using proteomic and RT-qPCR approaches, we investigated how Pseudomonas aeruginosa adapts the level of expression of its various iron-uptake pathways in response to different growth conditions (planktonic growth in different media and an epithelial cells infection assay) in the presence and absence of four different exosiderophores. The results show a complex phenotypic plasticity in the expression of the various iron-uptake pathways indicating a high potential of adaptation of P. aeruginosa to a large variety of biotopes. Graphical Abstract Highlights P. aeruginosa grown with exosiderophores and analyzed by proteomic and RT-qPCR. Catechol-type exosiderophores strongly induce the expression of their transporters. Repression of the endogenous iron uptake pathways. Complex phenotypic plasticity in the expression of the various iron-uptake pathways. Bacteria secrete siderophores to access iron, a key nutrient poorly bioavailable and the source of strong competition between microorganisms in most biotopes. Many bacteria also use siderophores produced by other microorganisms (exosiderophores) in a piracy strategy. Pseudomonas aeruginosa, an opportunistic pathogen, produces two siderophores, pyoverdine and pyochelin, and is also able to use a panel of exosiderophores. We first investigated expression of the various iron-uptake pathways of P. aeruginosa in three different growth media using proteomic and RT-qPCR approaches and observed three different phenotypic patterns, indicating complex phenotypic plasticity in the expression of the various iron-uptake pathways. We then investigated the phenotypic plasticity of iron-uptake pathway expression in the presence of various exosiderophores (present individually or as a mixture) under planktonic growth conditions, as well as in an epithelial cell infection assay. In all growth conditions tested, catechol-type exosiderophores were clearly more efficient in inducing the expression of their corresponding transporters than the others, showing that bacteria opt for the use of catechol siderophores to access iron when they are present in the environment. In parallel, expression of the proteins of the pyochelin pathway was significantly repressed under most conditions tested, as well as that of proteins of the pyoverdine pathway, but to a lesser extent. There was no effect on the expression of the heme and ferrous uptake pathways. Overall, these data provide precise insights on how P. aeruginosa adjusts the expression of its various iron-uptake pathways (phenotypic plasticity and switching) to match varying levels of iron and competition.
Nano-in-Micro Dual Delivery Platform for Chronic Wound Healing Applications

Here, we developed a combinatorial delivery platform for chronic wound healing applications. A microfluidic system was utilized to form a series of biopolymer-based microparticles with enhanced affinity to encapsulate and deliver vascular endothelial growth factor (VEGF). Presence of heparin into the structure can significantly increase the encapsulation efficiency up to 95% and lower the release rate of encapsulated VEGF. Our in vitro results demonstrated that sustained release of VEGF from microparticles can promote capillary network formation and sprouting of endothelial cells in 2D and 3D microenvironments. These engineered microparticles can also encapsulate antibiotic-loaded nanoparticles to offer a dual delivery system able to fight bacterial infection while promoting angiogenesis. We believe this highly tunable drug delivery platform can be used alone or in combination with other wound care products to improve the wound healing process and promote tissue regeneration.
Risk Factors Associated With Cesarean Delivery After Induction of Labor in Women With Class III Obesity.

OBJECTIVE To assess the risk factors associated with cesarean delivery in women with class III obesity (body mass index [BMI, calculated as weight in kilograms divided by height in meters squared] 40 or higher) who are undergoing induction of labor. METHODS This was a retrospective cohort of obese women with a BMI of 40 or higher and singleton pregnancy of 34 weeks of gestation or longer who underwent induction of labor at two large teaching institutions from January 2013 to December 2015. The primary outcome was cesarean delivery. Secondary outcomes included maternal and neonatal composite morbidity. We then assessed the applicability of using a previously developed calculator to predict the risk of cesarean delivery. The area under the receiver operating characteristic (ROC) curve was used as a measure of the ability of the calculator to discriminate between women who underwent cesarean compared with vaginal delivery. RESULTS There were 485 women with class III obesity who underwent induction during the study period. Of the 428 women who met inclusion criteria, 81.8% had a BMI of 40-50, 14.5% had a BMI of 50-60, and 3.7% had a BMI higher than 60. The overall cesarean delivery rate was 49.1% (46% with BMI 40-50, 63% with BMI 50-60, and 69% with BMI higher than 60, P=.012). Of the 428 women studied, 77.6% were black and 55% were nulliparous. Nulliparity, height, initial cervical dilation, and modified Bishop score were associated with a higher rate of cesarean delivery in multivariable models. Maternal and neonatal composite morbidity was higher in obese women who underwent cesarean delivery, compared with those who delivered vaginally. The performance of a previously developed induction calculator applied to this cohort had an area under the ROC curve of 75% (95% CI 0.70-0.79). CONCLUSIONS In women with class III obesity who underwent labor induction, the cesarean delivery rate approaches 50%. Nulliparity, height, and unfavorable cervical examination were the most significant risk factors for cesarean delivery. This information can be used to augment counseling for the obese patient who is undergoing induction.