Efficacy of dupilumab on chronic rhinosinusitis with nasal polyps and concomitant asthma in biologic-naive and biologic-pretreated patients.

OBJECTIVES: Dupilumab, an anti-IL-4 receptor monoclonal antibody (mAb), was recently approved for the treatment of severe chronic rhinosinusitis with nasal polyps (CRSwNP). The main objective of this study was to assess whether previous exposure to biological treatment affected the clinical outcomes in CRSwNP and asthma patients, treated with dupilumab over time. A collateral secondary objective was to analyse the effects over time of dupilumab in patients with and without aeroallergen sensitization. METHODS: Single-centre retrospective observational study on severe CRSwNP patients treated with dupilumab. Nasal polyp score (NPS), visual analogue scale (VAS) symptom score, sinonasal outcome test (SNOT-22), aeroallergen sensitization, total serum IgE levels, and blood eosinophil counts were assessed at baseline and after 4, 6 and 12 months. RESULTS: 42 patients were included, 40 (95.2%) had asthma. Twenty-one (50%) patients received dupilumab without prior biological treatment (Group A: naive) and 50% switched to dupilumab from previous biological treatment (Group B: pre-treated). NPS, VAS symptoms, SNOT-22 improved significantly after 12 months treatment in both groups of patients (p < 0.001). After 12 months, VAS overall symptom score showed a significant reduction from 6 (IQR, 4.6-8.6) and 6 (IQR, 3.8-7.1) for Group A and Group B patients respectively, to 1.2 (IQR, 0.8-2.7) and 1.2 (IQR, 0.2-2.5); NPS from 6 (IQR, 4.0-7.0) and 5 (IQR, 3.5-6.0), respectively, to 1 (IQR, 0.0-2.0) and 0 (IQR, 0.0-3.0) and SNOT-22 from 64 (IQR, 56-78) and 71 (IQR, 47.5-76.0) respectively, to 5.5 (IQR, 4-21) and 6 (IQR, 4-15). IgE reduced from 57 to 22.1 and from 46.9 to 30.2 in Group A and Group B respectively (p < 0.001). CONCLUSIONS: Dupilumab improves symptom severity, polyp size, and health-related quality of life, regardless of the presence or absence of comorbid aeroallergen sensitization and previous administration of biologic therapy.

Dupilumab proved to be effective in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP).We observed that dupilumab for CRSwNP leads to a very rapid improvement in polyps, symptoms, and quality of life, regardless of previous biologic treatment status and presence or absence of allergic rhinitis.VAS, SNOT-22 and NPS may be established as outcome markers in everyday clinical practice during dupilumab treatment.

Improving the nutritional evaluation in head neck cancer patients using bioelectrical impedance analysis: Not only the phase angle matters.

BACKGROUND: Malnutrition and sarcopenia are highly prevalent in patients with head neck cancer (HNC). An accurate early diagnosis is necessary for starting nutritional support, as both are clearly associated with clinical outcomes and mortality. We aimed to evaluate the applicability and accuracy of body composition analysis using electrical bioimpedance vectorial analysis (BIVA) for diagnosing malnutrition and sarcopenia in patients with HNC cancer undergoing systemic treatment with chemotherapy or radiotherapy. METHODS: Cross-sectional, observational study that included 509 HNC patients. A comprehensive nutritional evaluation that included BIVA was performed. RESULTS: The prevalence of malnutrition was higher in patients that received treatment with chemotherapy (59.2% vs. 40.8%, P < 0.001); increased mortality was observed in malnourished patients (33.3% vs. 20.1%; P < 0.001); ECOG status (1-4) was also worse in malnourished patients (59.2% vs. 22.8% P < 0.001). Body cell mass (BCM) and fat mass were the most significantly associated parameters with malnutrition [OR 0.88 (0.84-0.93) and 0.98 (0.95-1.01), respectively]; BCM and fat free mass index (FFMI) were associated with several aspects including (1) the patient-generated subjective global assessment [OR 0.93 (0.84-0.98) and 0.86 (0.76-0.97), respectively], (2) the presence of sarcopenia [OR 0.81 (0.76-0.87) and 0.78 (0.66-0.92), respectively]. A BCM index (BCMI) < 7.8 in combination with other parameters including FFMI and BCM accurately predicted patients with malnutrition [accuracy 95% CI: 0.803 (0.763-0.839); kappa index: 0.486; AUC: 0.618 (P < 0.01)]. A BCMI cutoff of 7.6 was enough for identifying males with malnutrition (P < 0.001), while it should be combined with other parameters in females. CONCLUSIONS: Body composition parameters determined by BIVA accurately identify patients with HNC and malnutrition. Phase angle, but other parameters including BCMI, FFMI and BCM provide significant information about nutritional status in patients with HNC.

Multicenter study on Clostridioides difficile infections in Mexico: exploring the landscape.

OBJECTIVE: This study aims to outline Clostridioides difficile infection (CDI) trends and outcomes in Mexican healthcare facilities during the COVID-19 pandemic. DESIGN: Observational study of case series. SETTING: Sixteen public hospitals and private academic healthcare institutions across eight states in Mexico from January 2016 to December 2022. PATIENTS: CDI patients. METHODS: Demographic, clinical, and laboratory data of CDI patients were obtained from clinical records. Cases were classified as community or healthcare-associated infections, with incidence rates calculated as cases per 10,000 patient days. Risk factors for 30-day all-cause mortality were analyzed by multivariate logistic regression. RESULTS: We identified 2,356 CDI cases: 2,118 (90%) were healthcare-associated, and 232 (10%) were community-associated. Common comorbidities included hypertension, diabetes, and cancer. Previous high use of proton-pump inhibitors, steroids, and antibiotics was observed. Recurrent infection occurred in 112 (5%) patients, and 30-day mortality in 371 (16%). Risk factors associated with death were a high Charlson score, prior use of steroids, concomitant use of antibiotics, leukopenia, leukocytosis, elevated serum creatine, hypoalbuminemia, septic shock or abdominal sepsis, and SARS-CoV-2 coinfection. The healthcare-associated CDI incidence remained stable at 4.78 cases per 10,000 patient days during the pre-and pandemic periods. However, the incidence was higher in public hospitals. CONCLUSIONS: Our study underscores the need for routine epidemiology surveillance and standardized CDI classification protocols in Mexican institutions. Though CDI rates in our country align with those in some European countries, disparities between public and private healthcare sectors emphasize the importance of targeted interventions.

[A 49-year-old woman with long-standing urinary symptoms. Histological and immunohistochemical study of a case of bladder mullerianosis]. / Mujer de 49 años con clínica urinaria de larga evolución. Estudio histológico e inmunohistoquímico de un caso de mullerianosis vesical.

Bladder müllerianosis is defined by the presence of Müllerian epithelium (endometrial, endocervical or endosalpinx) in the bladder. It is a rare benign disease that affects women and presents a non-specific clinical presentation that poses a broad differential diagnosis. We present the case of a 49-year-old woman who presented with recurrent urinary tract infections, urinary discomfort and abdominal pain. The approach is carried out by ultrasound and urethrocystoscopy that reveal the presence of a 5mm polypoid lesion that is removed. The histological study revealed bladder müllerianosis together with the complementary finding of glandular cystitis and cystic cystitis.

Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis.

Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e., GLUT1, for brain glucose metabolism has not been defined. Unexpectedly, we found that brain glucose metabolism was paradoxically augmented in mice with astrocytic GLUT1 reduction (GLUT1ΔGFAP mice). These mice also exhibited improved peripheral glucose metabolism especially in obesity, rendering them metabolically healthier. Mechanistically, we observed that GLUT1-deficient astrocytes exhibited increased insulin receptor-dependent ATP release, and that both astrocyte insulin signaling and brain purinergic signaling are essential for improved brain function and systemic glucose metabolism. Collectively, we demonstrate that astrocytic GLUT1 is central to the regulation of brain energetics, yet its depletion triggers a reprogramming of brain metabolism sufficient to sustain energy requirements, peripheral glucose homeostasis, and cognitive function.

Fumonisins in infant cereals marketed as complementary food in Argentina.

Infant cereals are typically the first foods introduced as complementary foods. Cereals used to elaborate complementary foods, such as wheat, maize and rice, are susceptible to mycotoxin contamination. Among mycotoxins, fumonisins have been epidemiologically associated, in humans, with oesophageal cancer, neural tube defects and stunting. Fumonisins have been found in maize and wheat grains in Argentina. In the present study, a survey was conducted to determine their occurrence in 82 wheat-based and multicereal-based infant cereal items collected from retail stores in Rio Cuarto, Argentina, using HPLC-MS. Of these samples, 84% showed FBs contamination with levels ranging from 0.05 to 992 µg/kg). Although FB1 was the most prevalent fumonisin, FB2 was found at higher levels. Most samples had levels below the limit of 200 µg/kg set for Argentinean cereal products for children. The outcome of this survey provides information on the naturally presence of fumonisin in infant cereal intended for children in Argentina, which can be helpful to consider relevant monitoring programmes.

Defects or no defects? Or how to design 20-25 nm spherical iron oxide nanoparticles to harness both magnetic hyperthermia and photothermia.

Designing iron oxide nanoparticles (IONPs) to effectively combine magnetic hyperthermia (MH) and photothermia (PTT) in one IONP formulation presents a significant challenge to ensure a multimodal therapy allowing the adaptation of the treatment to each patient. Recent research has highlighted the influence of factors such as the size, shape, and amount of defects on both therapeutic approaches. In this study, 20-25 nm spherical IONPs with a spinel composition were synthesized by adapting the protocol of the thermal decomposition method to control the amount of defects. By tuning different synthesis parameters such as the precursor nature, the introduction of a well-known oxidizing agent, dibenzylether (DBE), in the reaction medium, the heating rate and duration and the introduction of a nucleation step, we thus established two different synthesis protocols, one involving the use of a small amount of DBE leading to IONPs with only a few defects and another that took an optimized route to oxidize the wüstite nuclei during the IONP growth and led to IONPs exhibiting more structural and oxygen defects. IONPs exhibiting fewer defects showed enhanced MH and PTT heating values even when immobilized in a matrix, despite a decrease in MH heating values showing that they release mainly heat through the Brownian mechanism. These MH measurements have also confirmed that defects play a key role in enhancing Néel relaxation. PTT measurements demonstrated higher heating values with IONPs with fewer defects and a correlation between Urbach energy and SAR values suggesting an impact of vacancy defects on PTT performances. Therefore, IONPs exhibiting fewer defects under our synthesis conditions appear as suitable IONPs to combine both MH and PTT treatments with high performances. These findings pave the way for promising applications in combined therapies for cancer treatment.

Pituitary Apoplexy: Comorbidities, Management and Outcomes. A Spanish Observational Multicenter Study.

BACKGROUND: Pituitary apoplexy (PA) is the paradigm of endocrine and neurosurgical emergency. OBJECTIVE: To evaluate the comorbidities, risk factors, clinical presentation, pituitary apoplexy score (PAS) and the outcomes of surgical vs. conservative management of PA in Spain. METHODS: Spanish multicenter, observational study of 301 patients with acute PA. Statistical analyses compared risk factors, clinical presentation and outcomes between the surgical and conservative treatment groups, adjusting for potential confounders. The prevalence of cardiovascular risk factors in patients with pituitary apoplexy was compared with the Spanish population and with patients with non-functioning pituitary adenomas. RESULTS: Median age was 59.3 years, 201 (66.8%) were men and non-functioning adenomas (77.9%) were the most common tumor type. The prevalence of diabetes (20.3% vs 13.9%, p<0.01), hypertension (48.8% vs 33.4%, p<0.01) and dyslipidemia (44.2% vs 23.3%, p<0.01), exceeded the Spanish age-adjusted population prevalence. Overall, 209 (69.4%) underwent surgery and 92 (30.6%) received conservative treatment. Surgical patients had larger tumors (26.2 vs 21.0 mm, p<0.01), chiasmal compression more frequently (77.2% vs 53.4%, p<0.01) and higher values of PAS. In the follow-up, while there were no statistically significant differences in anterior pituitary hormonal deficits between treatments, permanent vasopressin deficiency was more frequent after surgery (14.8% vs 3.3%, p<0.01). CONCLUSION: There is a high burden of cardiovascular risk factors among patients with PA suggesting that metabolic factors may play a potential role in the development of PA. This underscores the need for comprehensive management of these conditions in addition to treating the apoplexy itself in this population. Surgical management has a relevant place in PA approach mainly in patients with higher PAS. However, it leads permanent vasopressin deficit more frequently than conservative approach.

Discrepancy in opioid prescription patterns for Black or African American patients following lower extremity bypass surgery for chronic limb-threatening ischemia.

BACKGROUND: Disparity in the allocation of medical services and resources based on race is present within the health care industry today, including the prescription of postoperative analgesics. The purpose of this study was to evaluate the presence of race-based disparity in the prescription of postdischarge opioids after lower extremity bypass (LEB) surgery for chronic limb-threatening ischemia (CLTI). METHODS: Retrospective analysis was conducted on adult CLTI patients who underwent LEB from 2000 to 2023 in the TrinetX database. Patients were stratified into two groups based on race: White (group I) and black or African American (AA) (group II). Primary outcomes were defined as oral opioid prescriptions at 7 days and 30 days after discharge, and mortality at 1 year postoperatively. Secondary outcomes included length of stay and 30-day postoperative outcomes, including myocardial infarction, pulmonary embolism, cerebral vascular accident, deep vein thrombosis, acute kidney injury, major amputation, minor amputation, major adverse cardiac events, and major adverse limb events. Stratified analysis was conducted based on disease stage (rest pain vs lower extremity ulcer vs gangrene). Univariate analysis was performed via two-sample t test and χ2 test. Logistic regression was performed to estimate the association of Black or AA (vs White) race while controlling for pertinent preoperative potential confounders. RESULTS: There were 3345 patients who met the inclusion criteria. Group I included 2661 White patients and group II included 684 Black or AA patients. Group II patients were more likely to be younger, female, present with gangrene, and have a history of hypertension, diabetes, chronic kidney disease, or diabetic neuropathy. At both 7 and 30 days after discharge, the Black or AA cohort had significantly lower rates of opioid prescriptions (33.2% vs 42.5% and 35.8% vs 47.2%, respectively) (all P < .05). Stratification by indication showed that opioid prescription disparity persisted despite black or AA patients presenting at worse stages of disease both at 7 and 30 days after discharge (7 days: rest pain 43.4% vs 33.7% [P = .013], ulcer 41.4% vs 31.7% [P = .027], gangrene, 42.7% vs 33.6% [P = .006] and 30 days: rest pain 47.8% vs 37.1% [P = .007], ulcer 45.4% vs 33.5% [P = .007], gangrene, 48.2% vs 36.1% [P < .001]). Adjusted analysis confirmed that Black or AA race was associated with lower rates of 7- (adjusted odds ratio, 0.607; P = .001) and 30-day (adjusted odds ratio, 0.56; P = .001) postdischarge opioid prescriptions. CONCLUSIONS: Black or AA patients were less likely to receive postdischarge opioid prescriptions compared with their White counterparts at 7 and 30 days after LEB for CLTI.

Comparative effectiveness of perioperative physical activity in older adults with lung cancer and their family caregivers: design of a multicenter pragmatic randomized trial.

BACKGROUND: With a median age at diagnosis of 70, lung cancer remains a significant public health challenge for older Americans. Surgery is a key component in treating most patients with non-metastatic lung cancer. These patients experience postoperative pain, fatigue, loss of respiratory capacity, and decreased physical function. Data on quality of life (QOL) in older adults undergoing lung cancer surgery is limited, and few interventions are designed to target the needs of older adults and their family caregivers (FCGs). The primary aim of this comparative effectiveness trial is to determine whether telephone-based physical activity coaching before and after surgery will be more beneficial than physical activity self-monitoring alone for older adults and their FCGs. METHODS: In this multicenter comparative effectiveness trial, 382 older adults (≥ 65 years) with lung cancer and their FCGs will be recruited before surgery and randomized to either telephone-based physical activity coaching or physical activity self-monitoring alone. Participants allocated to the telephone-based coaching comparator will receive five telephone sessions with coaches (1 pre and 4 post surgery), an intervention resource manual, and a wristband pedometer. Participants in the self-monitoring only arm will receive American Society of Clinical Oncology (ASCO) physical activity information and wristband pedometers. All participants will be assessed at before surgery (baseline), at discharge, and at days 30, 60, and 180 post-discharge. The primary endpoint is the 6-minute walk test (6MWT) at 30 days post-discharge. Geriatric assessment, lower extremity function, self-reported physical function, self-efficacy, and QOL will also be assessed. DISCUSSION: The trial will determine whether this telephone-based physical activity coaching approach can enhance postoperative functional capacity and QOL outcomes for older adults with lung cancer and their FCGs. Trial results will provide critical findings to inform models of postoperative care for older adults with cancer and their FCGs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06196008.

Tailoring the pore structure of iron oxide core@stellate mesoporous silica shell nanocomposites: effects on MRI and magnetic hyperthermia properties and applicability to anti-cancer therapies.

Core-shell nanocomposites made of iron oxide core (IO NPs) coated with mesoporous silica (MS) shells are promising theranostic agents. While the core is being used as an efficient heating nanoagent under alternating magnetic field (AMF) and near infra-red (NIR) light and as a suitable contrast agent for magnetic resonance imaging (MRI), the MS shell is particularly relevant to ensure colloidal stability in a biological buffer and to transport a variety of therapeutics. However, a major challenge with such inorganic nanostructures is the design of adjustable silica structures, especially with tunable large pores which would be useful, for instance, for the delivery of large therapeutic biomolecule loading and further sustained release. Furthermore, the effect of tailoring a porous silica structure on the magneto- or photothermal dissipation still remains poorly investigated. In this work, we undertake an in-depth investigation of the growth of stellate mesoporous silica (STMS) shells around IO NPs cores and of their micro/mesoporous features respectively through time-lapse and in situ liquid phase transmission electron microscopy (LPTEM) and detailed nitrogen isotherm adsorption studies. We found here that the STMS shell features (thickness, pore size, surface area) can be finely tuned by simply controlling the sol-gel reaction time, affording a novel range of IO@STMS core@shell NPs. Finally, regarding the responses under alternating magnetic fields and NIR light which are evaluated as a function of the silica structure, IO@STMS NPs having a tunable silica shell structure are shown to be efficient as T2-weighted MRI agents and as heating agents for magneto- and photoinduced hyperthermia. Furthermore, such IO@STMS are found to display anti-cancer effects in pancreatic cancer cells under magnetic fields (both alternating and rotating).

Ibrutinib in Combination with R-GemOx in Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma of Nongerminal Center B-cell-like Type: Phase II Clinical Trial of the Spanish GELTAMO Group.

PURPOSE: This phase II clinical trial evaluated the combination of ibrutinib with rituximab, gemcitabine, and oxaliplatin (R-GemOx) in patients with nongerminal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: The IBDCL trial (NCT02692248) included patients with histologic diagnosis of non-GCB DLBCL with relapsed or refractory disease and non-candidates for stem-cell transplantation. Patients received an induction treatment consisting of six or eight cycles of R-GemOx at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. The primary objective was to evaluate the overall response rate after four cycles. RESULTS: Sixty-four patients were included, 72% of them refractory to the last regimen. The overall response rate and complete remission rate after the fourth cycle were 53% [95% confidence interval (CI), 41-65] and 34% (95% CI, 24-46), respectively. Twenty-four (37%) patients started maintenance, and 7 (11%) completed the planned 2 years. After a median follow-up of 29.7 months (range: 0.4-48.6), the estimated 2-year progression-free survival and overall survival were 18% (95% CI, 8-28) and 26% (95% CI, 14-37), respectively. The most common grade ≥3 treatment-related adverse events were thrombocytopenia (44%), neutropenia (30%), and anemia (14%). Grade ≥3 infectious and cardiovascular treatment-related adverse events were reported in 6 (9%) and 1 (2%) patient, respectively. CONCLUSIONS: Ibrutinib in combination with R-GemOx, followed by ibrutinib maintenance, demonstrated encouraging antitumor activity with durable responses and a manageable toxicity in patients with non-GCB DLBCL.

Preliminary Screening on Antibacterial Crude Secondary Metabolites Extracted from Bacterial Symbionts and Identification of Functional Bioactive Compounds by FTIR, HPLC and Gas Chromatography-Mass Spectrometry.

Secondary metabolites, bioactive compounds produced by living organisms, can unveil symbiotic relationships in nature. In this study, soilborne entomopathogenic nematodes associated with symbiotic bacteria (Xenorhabdus stockiae and Photorhabdus luminescens) were extracted from solvent supernatant containing secondary metabolites, demonstrating significant inhibitory effects against E. coli, S. aureus, B. subtilus, P. mirabilis, E. faecalis, and P. stutzeri. The characterization of these secondary metabolites by Fourier transforms infrared spectroscopy revealed amine groups of proteins, hydroxyl and carboxyl groups of polyphenols, hydroxyl groups of polysaccharides, and carboxyl groups of organic acids. Furthermore, the obtained crude extracts were analyzed by high-performance liquid chromatography for the basic identification of potential bioactive peptides. Gas chromatography-mass spectrometry analysis of ethyl acetate extracts from Xenorhabdus stockiae identified major compounds including nonanoic acid derivatives, proline, paromycin, octodecanal derivatives, trioxa-5-aza-1-silabicyclo, 4-octadecenal, methyl ester, oleic acid, and 1,2-benzenedicarboxylicacid. Additional extraction from Photorhabdus luminescens yielded functional compounds such as indole-3-acetic acid, phthalic acid, 1-tetradecanol, nemorosonol, 1-eicosanol, and unsaturated fatty acids. These findings support the potential development of novel natural antimicrobial agents for future pathogen suppression.

ATTRv-V30M Type A amyloid fibrils from heart and nerves exhibit structural homogeneity.

ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid hormones. Transthyretin is primarily produced by the liver and circulates in blood as a tetramer. The retinal epithelium also secretes transthyretin, which is secreted to the vitreous humor of the eye. Because of mutations or aging, transthyretin can dissociate into amyloidogenic monomers triggering amyloid fibril formation. The deposition of transthyretin amyloid fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively. Using cryo-electron microscopy, here we determined the structures of amyloid fibrils extracted from cardiac and nerve tissues of an ATTRv-V30M patient. We found that fibrils from both tissues share a consistent structural conformation, similar to the previously described structure of cardiac fibrils from an individual with the same genotype, but different from the fibril structure obtained from the vitreous humor. Our study hints to a uniform fibrillar architecture across different tissues within the same individual, only when the source of transthyretin is the liver. Moreover, this study provides the first description of ATTR fibrils from the nerves of a patient and enhances our understanding of the role of deposition site and protein production site in shaping the fibril structure in ATTRv-V30M amyloidosis.

Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant.

ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in the form of amyloid fibrils into various organs. ATTR amyloidosis may stem from mutations in variant (ATTRv) amyloidosis, or aging in wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as a cardiomyopathy phenotype, whereas ATTRv may present as polyneuropathy, cardiomyopathy, or mixed, in combination with many other symptoms deriving from secondary organ involvement. Over 130 different mutational variants of transthyretin have been identified, many of them being linked to specific disease symptoms. Yet, the role of these mutations in the differential disease manifestation remains elusive. Using cryo-electron microscopy, here we structurally characterized fibrils from the heart of an ATTRv patient carrying the V122Δ mutation, predominantly associated with polyneuropathy. Our results show that these fibrils are polymorphic, presenting as both single and double filaments. Our study alludes to a structural connection contributing to phenotypic variation in ATTR amyloidosis, as polymorphism in ATTR fibrils may manifest in patients with predominantly polyneuropathic phenotypes.

Multi-organ structural homogeneity of amyloid fibrils in ATTRv-T60A amyloidosis patients, revealed by Cryo-EM.

ATTR amyloidosis is a degenerative disorder characterized by the systemic deposition of the protein transthyretin. These amyloid aggregates of transthyretin (ATTR) can deposit in different parts of the body causing diverse clinical manifestations. Our laboratory aims to investigate a potential relationship between the different genotypes, organ of deposition, clinical phenotypes, and the structure of ATTR fibrils. Using cryo-electron microscopy, we have recently described how the neuropathic related mutations ATTRv-I84S and ATTRv-V122∆ can drive structural polymorphism in ex vivo fibrils. Here we question whether the mutation ATTRv-T60A, that commonly triggers cardiac and neuropathic symptoms, has a similar effect. To address this question, we extracted and determined the structure of ATTR-T60A fibrils from multiple organs (heart, thyroid, kidney, and liver) from the same patient and from the heart of two additional patients. We have found a consistent conformation among all the fibril structures, acquiring the "closed-gate morphology" previously found in ATTRwt and others ATTRv related to cardiac or mixed manifestations. The closed-gate morphology is composed by two segments of the protein that interact together forming a polar channel, where the residues glycine 57 to isoleucine 68 act as a gate of the polar cavity. Our study indicates that ATTR-T60A fibrils present in peripheral organs adopt the same structural conformation in all patients, regardless of the organ of deposition.

EGFR-ERK1/2 signaling and mitochondrial dynamics in seasonal ovarian steroidogenesis of the muskrats (Ondatra zibethicus).

The dynamic systems of mitochondria, including mitochondrial fusion and fission, are essential for ovarian endocrine and follicular development. Meanwhile, ERK1/2 signaling is an important mechanism mediating altered mitochondrial dynamics and steroidogenesis. The purpose of this study was to investigate the seasonal changes in ovarian steroidogenesis concerning EGFR-ERK1/2 signaling and mitochondrial dynamics of the muskrats (Ondatra zibethicus). The results showed that follicular development in the muskrats remained in the tertiary follicular stage during the non-breeding season, accompanied by a significant decrease in serum and ovarian concentrations of 17ß-estradiol and progesterone from the breeding season to the non-breeding season. EGF, EGFR, ERK1/2, p-ERK1/2, and mitochondrial dynamics regulators were mainly localized in granulosa cells and theca cells of muskrats during the breeding and non-breeding seasons. The mRNA levels of Egfr, Erk1/2, Mfn1/2, Opa1, Drp1, and steroidogenic enzymes in the ovaries were remarkably higher during the breeding season. The 17ß-estradiol concentrations in the serum and ovaries as well as the relative levels of Mfn1/2, Opa1, and Drp1 were positively associated with each other. Furthermore, transcriptomic analysis of the ovaries revealed that differentially expressed genes might be linked to steroid biosynthesis, estrogen signaling pathway, and mitochondrial membrane-related pathways. In conclusion, these results suggest that the up-regulation of mitochondrial dynamics regulators during the breeding season is closely associated with enhanced ovarian steroidogenesis in the muskrats, which may be regulated by upstream EGFR-ERK1/2 signaling.

Dynamics of virological and immunological markers of HIV persistence after allogeneic haematopoietic stem-cell transplantation in the IciStem cohort: a prospective observational cohort study.

BACKGROUND: Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) markedly reduces HIV reservoirs, but the mechanisms by which this occurs are only partly understood. In this study, we aimed to describe the dynamics of virological and immunological markers of HIV persistence after allo-HSCT. METHODS: In this prospective observational cohort study, we analysed the viral reservoir and serological dynamics in IciStem cohort participants with HIV who had undergone allo-HSCT and were receiving antiretroviral therapy, ten of whom had received cells from donors with the CCR5Δ32 mutation. Participants from Belgium, Canada, Germany, Italy, the Netherlands, Spain, Switzerland, and the UK were included in the cohort both prospectively and retrospectively between June 1, 2014 and April 30, 2019. In the first 6 months after allo-HSCT, participants had monthly assessments, with annual assessments thereafter, with the protocol tailored to accommodate for the individual health status of each participant. HIV reservoirs were measured in blood and tissues and HIV-specific antibodies were measured in plasma. We used the Wilcoxon signed-rank test to compare data collected before and after allo-HSCT in participants for whom longitudinal data were available. When the paired test was not possible, we used the Mann-Whitney U test. We developed a mathematical model to study the factors influencing HIV reservoir reduction in people with HIV after allo-HSCT. FINDINGS: We included 30 people with HIV with haematological malignancies who received a transplant between Sept 1, 2009 and April 30, 2019 and were enrolled within the IciStem cohort and included in this analysis. HIV reservoirs in peripheral blood were reduced immediately after full donor chimerism was achieved, generally accompanied by undetectable HIV-DNA in bone marrow, ileum, lymph nodes, and cerebrospinal fluid, regardless of donor CCR5 genotype. HIV-specific antibody levels and functionality values declined more slowly than direct HIV reservoir values, decaying significantly only months after full donor chimerism. Mathematical modelling suggests that allogeneic immunity mediated by donor cells is the main viral reservoir depletion mechanism after massive reservoir reduction during conditioning chemotherapy before allo-HSCT (half-life of latently infected replication-competent cells decreased from 44 months to 1·5 months). INTERPRETATION: Our work provides, for the first time, data on the effects of allo-HSCT in the context of HIV infection. Additionally, we raise the question of which marker can serve as the last reporter of the residual viraemia, postulating that the absence of T-cell immune responses might be a more reliable marker than antibody decline after allo-HSCT. FUNDING: amfAR (American Foundation for AIDS Research; ARCHE Program), National Institutes of Health, National Institute of Allergy and Infectious Diseases, and Dutch Aidsfonds.