New insights into the structure and function of the complex between the Escherichia coli Hsp70, DnaK, and its nucleotide-exchange factor, GrpE.

The 70 kDa heat shock proteins (Hsp70s) play a pivotal role in many cellular functions using allosteric communication between their nucleotide-binding domain (NBD) and substrate-binding domain, mediated by an interdomain linker, to modulate their affinity for protein clients. Critical to modulation of the Hsp70 allosteric cycle, nucleotide-exchange factors (NEFs) act by a conserved mechanism involving binding to the ADP-bound NBD and opening of the nucleotide-binding cleft to accelerate the release of ADP and binding of ATP. The crystal structure of the complex between the NBD of the Escherichia coli Hsp70, DnaK, and its NEF, GrpE, was reported previously, but the GrpE in the complex carried a point mutation (G122D). Both the functional impact of this mutation and its location on the NEF led us to revisit the DnaK NBD/GrpE complex structurally using AlphaFold modeling and validation by solution methods that report on protein conformation and mutagenesis. This work resulted in a new model for the DnaK NBD in complex with GrpE in which subdomain IIB of the NBD rotates more than in the crystal structure, resulting in an open conformation of the nucleotide-binding cleft, which now resembles more closely what is seen in other Hsp/NEF complexes. Moreover, the new model is consistent with the increased ADP off-rate accompanying GrpE binding. Excitingly, our findings point to an interdomain allosteric signal in DnaK triggered by GrpE binding.

Communication, understanding and engagement of patients with pancreatic cancer at time of diagnosis.

BACKGROUND: Objectives: To investigate communication clarity and understanding at the time of pancreatic adenocarcinoma (PDAC) diagnosis and whether they can influence patient engagement and compliance. METHODS: Consecutive PDAC patients were enrolled at the time of diagnosis after obtaining informed consent in a single-center study. The patients completed a validated scale (PHE-s®), and the understanding rate was assessed using standardized tools. Patient compliance was evaluated, and the correlation between the PHE-s®, understanding, and compliance was calculated. RESULTS: Thirty patients were enrolled (15 female) with a mean age 64.4, 13 were metastatic. The mean visit time was 31 min, being longer if visiting doctor was an oncologist (p = 0.002). The engagement level was high in 70% of the patients, and all but one were compliant. The analysis of doctor-patient interactions showed a median of 121 conversational turns for doctors, 75 for patients, and 20 for caregivers (p < 0.0001), and the median percentage of speaking time was 77% for doctors, 13% for patients, and 2% for caregivers (p < 0.0001). Female caregivers spent more time speaking than did male caregivers (median 11.6% vs. 1.3%; p = 0.06). There were 290 instances of problematic understanding, most of which occurred during the taking of patients' personal medical history for doctors, while for patients and caregivers, these occurred mainly during the discussion of diagnosis/treatment (p < 0.0001). In a multivariable analysis, only origin from central or southern Italy was associated with high engagement (p = 0.0087). CONCLUSION: In this first attempt to measure clarity of communication and engagement in patients with PDAC, typical features of conversation and problematic understanding emerged, which deserves further investigation.

Treatment intensification following glucagon-like peptide-1 receptor agonists in type 2 diabetes: Comparative effectiveness analyses between different basal insulins. RESTORE-G real-world study.

AIM: To compare the effectiveness of different basal insulins (BI) prescribed as an add-on to or switch from glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy. MATERIALS AND METHODS: Retrospective, real-world data from electronic medical records of 32 Italian diabetes clinics were used, after propensity score adjustment, to compare effectiveness after 6 months of treatment with second- versus first-generation BI (2BI vs. 1BI) or glargine 300 U/ml versus degludec 100 U/ml (Gla-300 vs. Deg-100), when added to (ADD-ON) or in substitution of (SWITCH) GLP-1 RA. Only comparisons, including a minimum of 100 patients per group, were performed to ensure adequate robustness of the analyses. RESULTS: In the ADD-ON cohort (N = 700), greater benefits of 2BI versus 1BI were found in glycated haemoglobin {HbA1c; estimated mean difference: -0.32% [95% confidence interval (CI) -0.62; -0.02]; p = .04} and fasting blood glucose [FBG; -20.73 mg/dl (95% CI -35.62; -5.84); p = .007]. In the SWITCH cohort (N = 2097), greater benefits of 2BI versus 1BI were found in HbA1c [-0.22% (95% CI -0.42; -0.02); p = .03], FBG [-10.15 mg/dl (95% CI -19.04; -1.26); p = .03], and body weight [-0.67 kg (95% CI -1.30; -0.04); p = .04]. In the SWITCH cohort starting 2BI (N = 688), marked differences in favour of Gla-300 versus Deg-100 were documented in HbA1c [-0.89% (95% CI -1.26; -0.52); p < .001] and FBG [-17.89 mg/dl (95% CI -32.45; -3.33); p = .02]. Using propensity score matching as a sensitivity analysis, the benefit on HbA1c was confirmed [-0.55% (95% CI -1.02; -0.08); p = .02]. BI titration was suboptimal in all examined cohorts. CONCLUSIONS: 2BI are a valuable option to intensify GLP-1 RA therapy. Switching to Gla-300 versus Deg-100 was associated with greater HbA1c improvement.

Treatment intensification following glucagon-like peptide-1 receptor agonist in type 2 diabetes: Comparative effectiveness analyses between free vs. fixed combination of GLP-1 RA and basal insulin. RESTORE-G real-world study.

BACKGROUND AND AIMS: Add-on of basal insulin (BI) to intensify the ongoing therapy with glucagon-like peptide 1 receptor agonist (GLP-1 RA) is recommended, but it is unclear if free or fixed combination of BI and GLP-1 RA produce similar outcomes. A retrospective comparative effectiveness analysis of the add-on of glargine 300 U/mL (Gla-300) to ongoing GLP-1 RA vs. switch to fixed ratio combination of degludec and liraglutide (iDegLira) was performed. METHODS AND RESULTS: Real-world data collected in electronic medical records by 32 Italian diabetes clinics. Propensity score (PS) adjustment was applied to assess changes in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), body weight, and BI dose after 6 months from Gla-300 or iDegLira initiation. Compared to iDegLira group (N = 260), Gla-300+GLP-1 RA group (N = 255) had older age and higher levels of HbA1c (9.1 vs. 8.9%). After 6 months, statistically significant greater FBG improvement [estimated mean difference and 95% confidence intervals: -24.05 mg/dl (-37.04; -11.06; p = 0.0003) and BI dose increase [+0.03 U/kg (95%CI 0.00; 0.06); p = 0.009] were found in the free vs. fixed combination group, although low doses of BI (0.2 U/kg) were reached in both groups. Trends of larger HbA1c and body weight reductions with the free combination were also found, without reaching the statistical significance. CONCLUSION: Although inertia in insulin initiation and titration was documented in both groups, higher benefit on FBG control was obtained with free vs. fixed combination, likely due to a better titration of BI and GLP-1 RA.

Alginate-Based Carriers Loaded with Mulberry (Morus alba L.) Leaf Extract: A Promising Strategy for Prolonging 1-Deoxynojirimicyn (DNJ) Systemic Activity for the Nutraceutical Management of Hyperglycemic Conditions.

The iminosugar 1-deoxynojirimicyn (DNJ) contained in mulberry leaves has displayed systemic beneficial effects against disorders of carbohydrate metabolism. Nevertheless, its effect is impaired by the short half-life. Alginate-based carriers were developed to encapsulate a DNJ-rich mulberry extract: Ca-alginate beads, obtained by external gelation, and spray-dried alginate microparticles (SDMs). Mean size and distribution, morphology, drug loading, encapsulation efficiency, experimental yield, and release characteristics were determined for the two formulations. Ca-alginate beads and SDMs exhibited an encapsulation efficiency of about 54% and 98%, respectively, and a DNJ loading in the range of 0.43-0.63 µg/mg. The in vitro release study demonstrated the carriers' capability in controlling the DNJ release in acid and basic conditions (<50% in 5 h), due to electrostatic interactions, which were demonstrated by 1H-NMR relaxometry studies. Thus, alginate-based particles proved to be promising strategies for producing food supplements containing mulberry leaf extracts for the management of hyperglycemic state.

Slow Protein Dynamics Elicits New Enzymatic Functions by Means of Epistatic Interactions.

Protein evolution depends on the adaptation of these molecules to different functional challenges. This occurs by tuning their biochemical, biophysical, and structural traits through the accumulation of mutations. While the role of protein dynamics in biochemistry is well recognized, there are limited examples providing experimental evidence of the optimization of protein dynamics during evolution. Here we report an NMR study of four variants of the CTX-M ß-lactamases, in which the interplay of two mutations outside the active site enhances the activity against a cephalosporin substrate, ceftazidime. The crystal structures of these enzymes do not account for this activity enhancement. By using NMR, here we show that the combination of these two mutations increases the backbone dynamics in a slow timescale and the exposure to the solvent of an otherwise buried ß-sheet. The two mutations located in this ß-sheet trigger conformational changes in loops located at the opposite side of the active site. We postulate that the most active variant explores alternative conformations that enable binding of the more challenging substrate ceftazidime. The impact of the mutations in the dynamics is context-dependent, in line with the epistatic effect observed in the catalytic activity of the different variants. These results reveal the existence of a dynamic network in CTX-M ß-lactamases that has been exploited in evolution to provide a net gain-of-function, highlighting the role of alternative conformations in protein evolution.

Treatment intensification following glucagon-like peptide-1 receptor agonist treatment in type 2 diabetes: The RESTORE-G real-world study.

BACKGROUND AND AIMS: To assess intensification approaches with basal insulin (BI) following glucagon-like peptide-1 receptor agonist (GLP-1 RA) treatment in type 2 diabetes (T2D). METHODS AND RESULTS: Real-world data were collected in electronic medical records by 32 Italian diabetes clinics between 2011 and 2021. Primary endpoint was the proportion of insulin-naïve T2D patients treated with GLP-1 RA who initiated (add-on or switch) BI. Secondary endpoints were: treatment approaches, mean time to BI start, effectiveness and safety. Among 7,962 eligible patients, BI was prescribed to 3,164 (39.7%; 95%CI 38.7; 40.8): 67.6% switched to BI (22.1% also starting 1-3 injections of short-acting insulin), 22.7% added BI while maintaining GLP-1 RA, and 9.7% switched to a fixed-ratio combination of GLP-1 RA and BI (FRC). Median time since the first GLP-1 RA to BI/FRC prescription was 27.4 (IQ range 11.8-53.5) months. In this study 60.3% of patients did not start BI/FRC, among whom 15.2% intensified GLP-1 RA therapy with other oral agents. Effectiveness and safety were documented in all intensification approaches with BI/FRC, but HbA1c level at intensification time of ≥9.0% and suboptimal BI titration suggested clinical inertia. Use of second generation BI and add-on to GLP-1 RA schemes increased over time and effectiveness improved. CONCLUSION: Clinical inertia should be overcome using innovative insulin options. Timely combination therapy of BI and GLP-1 RA is a valuable choice.

Understanding COVID-19 vaccine hesitancy in the Hispanic adult population of South Carolina: a complex mixed-method design evaluation study.

BACKGROUND: In August 2021, only 47.6% of all eligible residents in South Carolina (SC) had received at least one dose of the COVID-19 vaccine, with only 41% having completed their vaccination series. Additionally, only 27% of all Hispanics in SC had completed their vaccination series compared to 34.1% of non-Hispanics. Vaccine hesitancy is a complex phenomenon that is context and vaccine-specific. Focusing on unvaccinated Hispanics living in rural areas of SC, this study aimed to identify barriers to vaccination and provide an educational intervention designed to address vaccine hesitancy. METHODS: A complex mixed-methods evaluation design was used to conduct this study. First, in-person vaccine educational sessions were implemented, along with a pre-post-test survey, to assess changes in knowledge, attitudes, motivations, barriers, and intentions to receive COVID-19 vaccination. Second, in-person follow-up focus groups were held with the same participants to gather in-depth insight about participants' knowledge and attitudes about the COVID-19 vaccination. Third, an online follow-up survey was conducted to assess the effect of the training and discussion session on COVID-19 vaccination. Study outcomes were assessed among the 17 individuals who participated in the educational sessions and focus group discussions. RESULTS: Findings revealed that for unvaccinated Hispanics living in South Carolina; vaccine hesitancy was primarily driven by: 1) misinformation and information coming from unverified sources and 2) negative perceptions of the safety and effectiveness of the COVID-19 vaccines. Specifically, participants were fearful that the vaccine development was rushed and that the vaccines might contain questionable ingredients that could cause strong side effects or even death. Participants were also concerned that vaccination might cause them to get sick and be hospitalized, which would have financial implications since they could not afford healthcare or take time off work. CONCLUSIONS: Program implementation and mass communication campaigns should focus on COVID-19 vaccine safety and effectiveness, including side effects, what to expect after being vaccinated, and how to look for information from reputable sources. The educational session implemented proved to be effective and helped reduce vaccine hesitancy since most participants (80%) self-reported receiving a COVID-19 vaccine after program participation.

Echocardiographic Markers of Mild Pulmonary Hypertension are not Correlated with Worse Respiratory Outcomes in Infants with Bronchiolitis.

Pulmonary hypertension has been reported as a crucial factor in the pathophysiology of severe bronchiolitis. The aim of this study was to evaluate pulmonary artery pressure (PAP) in patients with bronchiolitis and to analyze their correlation with clinical outcomes. This prospective cohort study examined children admitted for bronchiolitis. PAP was assessed by right ventricle (RV) acceleration/ejection time ratio (AT/ET), isovolumic relaxation time, eccentricity index, and the presence of a pulmonary systolic notch. Pulmonary hypertension (PH) was considered if at least two altered parameters were present. Severity of clinical course was established by higher N-terminal (NT)-prohormone BNP (NT-proBNP) values, the need for positive pressure respiratory support (PPRS), and the duration of hospital admission. One hundred sixty-nine children were included in analysis. Sixty-eight patients (40%) required PPRS, and those patients had increased NT-proBNP values and worse tricuspid annular systolic excursion (TAPSE) compared to mild cases (p < 0.001and p < 0.001, respectively). Twenty-two (13%) cases had at least two altered parameters of PAP and met criteria for presumed PH, with no differences in NT-proBNP values, TAPSE, need for PPRS or hospital length of stay compared to normal PAP group (p = 0.98, p = 0.07, p = 0.94 and p = 0.64, respectively). We found no correlation between altered RV AT/ET and worse cardiac function, NT-proBNP values or hospital length of stay. In our cohort, the presence of echocardiographic findings of PH were not associated with worse clinical outcomes. Patients with severe bronchiolitis had higher values ​​of NT-proBNP but, interestingly, no clear association with PH.

Nucleus-cytoskeleton communication impacts on OCT4-chromatin interactions in embryonic stem cells.

BACKGROUND: The cytoskeleton is a key component of the system responsible for transmitting mechanical cues from the cellular environment to the nucleus, where they trigger downstream responses. This communication is particularly relevant in embryonic stem (ES) cells since forces can regulate cell fate and guide developmental processes. However, little is known regarding cytoskeleton organization in ES cells, and thus, relevant aspects of nuclear-cytoskeletal interactions remain elusive. RESULTS: We explored the three-dimensional distribution of the cytoskeleton in live ES cells and show that these filaments affect the shape of the nucleus. Next, we evaluated if cytoskeletal components indirectly modulate the binding of the pluripotency transcription factor OCT4 to chromatin targets. We show that actin depolymerization triggers OCT4 binding to chromatin sites whereas vimentin disruption produces the opposite effect. In contrast to actin, vimentin contributes to the preservation of OCT4-chromatin interactions and, consequently, may have a pro-stemness role. CONCLUSIONS: Our results suggest roles of components of the cytoskeleton in shaping the nucleus of ES cells, influencing the interactions of the transcription factor OCT4 with the chromatin and potentially affecting pluripotency and cell fate.

Aspirin Affects MDA-MB-231 Vesicle Production and Their Capacity to Induce Fibroblasts towards a Pro-Invasive State.

Long-term administration of aspirin (ASA, acetylsalicylic acid) in oncogenic patients has been related to a reduction in cancer risk incidence, but its precise mechanism of action is unclear. The activation of cancer-associated fibroblasts (CAFs) is a key element in tumor progression and can be triggered by cancer-derived extracellular vesicles (EVs). Targeting the communication between cancer cells and the surrounding tumor microenvironment (TME) may control cancer progression. Our aim was to investigate the effect of ASA on breast cancer cells, focusing on EV secretion and their effect on the biological properties of CAFs. As a result, ASA was shown to reduce the amount and alter the size distribution of EVs produced by MDA-MB-231 tumor cells. Fibroblasts stimulated with EVs derived from MDA-MB-231 treated with ASA (EV-ASA) showed a lower expression of alpha-smooth muscle actin (α-SMA), matrix metalloproteinase-2 (MMP2) but not fibroblast activation protein (FAP) in respect to the ones stimulated with EVs from untreated breast cancer cells (EV-CTR). Furthermore, invasion assays using a three-dimensional (3D) fibroblast spheroid model showed reduced MDA-MB-231 invasion towards fibroblast spheroids pretreated with EV-ASA as compared to spheroids prepared with EV-CTR-stimulated fibroblasts. This suggests that ASA partially inhibits the ability of tumor EVs to stimulate CAFs to promote cancer invasion. In conclusion, ASA can interfere with tumor communication by reducing EV secretion by breast tumor cells as well as by interfering with their capacity to stimulate fibroblasts to become CAFs.

"Strada Facendo" a Series of Group Meetings with Parents of Children and Youths with Disabilities.

The article describes the psychological support offered to parents of disabled children/youths through the structuring of mutual self-help meetings. The therapeutic approach, which is based on the principles of the Family Centered Care (FCC), has an experiential character. These meetings are especially important as they took place after a long period of forced distancing, due to the Covid 19 pandemic. We can see how this type of path fully responds to the needs of these parents and how it can be strategic for strengthening their capacity for resilience in the daily struggle for the quality of life of their children.

Th17 lymphocyte-dependent degradation of joint cartilage by synovial fibroblasts in a humanized mouse model of arthritis and reversal by secukinumab.

How T-helper (Th) lymphocyte subpopulations identified in synovial fluid from patients with juvenile idiopathic arthritis (JIA) (Th17, classic Th1, or nonclassic Th1) drive joint damage is of great interest for the possible use of biological drugs that inhibit the specific cytokines. Our objective was to clarify the role of such Th subpopulations in the pathogenesis of articular cartilage destruction by synovial fibroblasts (SFbs), and the effect of Th17 blockage in an animal model. SFbs were isolated from healthy subjects and patients with JIA, and peripheral blood Th lymphocytes subsets were obtained from healthy subjects. Fragments of human cartilage from healthy subjects in a collagen matrix containing JIA or normal SFbs grafted underskin in SCID mice were used to measure cartilage degradation under the effects of Th supernatants. JIA SFbs overexpress MMP9 and MMP2 and Th17 induce both MMPs in normal SFbs, while nonclassic Th1 upregulate urokinase plasminogen activator (uPA) activity. In vitro invasive phenotype of normal SFbs is stimulated with conditioned medium of Th17 and nonclassic-Th1. In the in vivo "inverse wrap" model, normal SFbs stimulated with supernatants of Th17-lymphocytes and nonclassic Th1 produced a cartilage invasion and degradation similar to JIA SFbs. Secukinumab inhibits the cartilage damage triggered by factors produced by Th17.

Comparative effectiveness of Glargine 300 U/mL vs. Degludec 100 U/mL in patients with type 2 diabetes switching from 1° generation basal insulins.

BACKGROUND AND AIMS: Data on second generation basal insulin (2BI) in people with type 2 diabetes (T2D) generated by clinical trials still need confirmation in real-world clinical settings. This study aimed at assessing the comparative effectiveness of 2BI [Glargine 300 U/mL (Gla-300) vs. Degludec 100 U/mL (Deg-100)] in T2D Italian patients switching from first generation basal insulins (1BI). METHODS AND RESULTS: This was a retrospective, non-inferiority, multicenter study. Patients switching to Gla-300 or Deg-100 from 1BI were 1:1 propensity score matched (PSM). Changes during 6 months in continuous endpoints were assessed through linear mixed models. Incidence rates (IR) of hypoglycemia (episodes per patient-months) were compared using Poisson regression. Each PSM cohort included 593 patients. HbA1c decreased from baseline (8.7%) to 6 months by -0.58% (95%CI -0.69;-0.47) in Gla-300 group and -0.50% (95%CI -0.61;-0.39) in Deg-100 group, confirming the non-inferiority of Gla-300 vs. Deg-100. No between-group differences emerged: FBG was reduced by about 20 mg/dl with both 2BI, mean dose of 2BI (24.5 U, 0.3 U/Kg at the first prescription) was suboptimally titrated during 6 months (+1.34 U in Gla-300 and + 1.76 U in Deg-100), body weight showed minor changes. IR of hypoglycemia <54 mg/dl was 0.32 (95%CI 0.21; 0.49) in Gla-300 group and 0.19 (95%CI 0.11; 0.33) in Deg-100 group (p = 0.14). CONCLUSION: In subjects with T2D, switching to 2BI from 1BI was associated with similar improvements in glycemic control, low hypoglycemia rates and no weight gain in real-life setting. Clinical inertia, represented by late treatment intensification and suboptimal titration, represents a major issue in Italy.

Sex and gender differences in migraines: a narrative review.

INTRODUCTION: Gender medicine is a new medical approach aimed at the study of the differences between women and men in terms of prevention, diagnosis, and the outcome of all diseases. Migraines are among these. They represent the most common neurological illness; they are most prevalent in adults between 20 and 50 years of age and are three to four times more frequent in woman than in men. Affecting people in working age, migraines are a problem that strongly impacts the psychophysical health and productivity of workers, regardless of the specific job task they have. METHODS: A narrative review was performed, searching for the most relevant articles describing gender differences in people suffering from migraines, and particularly in workers. RESULTS: Migraine global prevalence is 20.7% in women and 9.7% in men whereas prevalence in Italy is 32.9% for women and only 13.0% for men. This difference is partly explained by hormonal differences, as well as by differences in brain structure, genetic polymorphisms and neuronal pathways. Sex differences may also play a role in the progression from episodic to chronic migraine. In workers, migraines are mostly associated with strenuous physical work in men, whilst migraines triggered by night shifts, lack of sleep, or irregular sleep patterns are more common in women. CONCLUSIONS: To this day, the reasons of sex/gender disparity for migraine are still obscure. However, migraines, chronic migraine in particular, have a negative impact on the lives of all individuals affected by this disease, but particularly in women in which family cares and working activity are often superimposed. Migraine prevention strategies should be planned in workers through the occupational health physician.

Investigation into cases of hepatitis of unknown aetiology among young children, Scotland, 1 January 2022 to 12 April 2022.

On 31 March 2022, Public Health Scotland was alerted to five children aged 3-5 years admitted to hospital with severe hepatitis of unknown aetiology. Retrospective investigation identified eight additional cases aged 10 years and younger since 1 January 2022. Two pairs of cases have epidemiological links. Common viral hepatitis causes were excluded in those with available results. Five children were adenovirus PCR-positive. Other childhood viruses, including SARS-CoV-2, have been isolated. Investigations are ongoing, with new cases still presenting.

A large multi-country outbreak of monkeypox across 41 countries in the WHO European Region, 7 March to 23 August 2022.

Following the report of a non-travel-associated cluster of monkeypox cases by the United Kingdom in May 2022, 41 countries across the WHO European Region have reported 21,098 cases and two deaths by 23 August 2022. Nowcasting suggests a plateauing in case notifications. Most cases (97%) are MSM, with atypical rash-illness presentation. Spread is mainly through close contact during sexual activities. Few cases are reported among women and children. Targeted interventions of at-risk groups are needed to stop further transmission.

Accurate Signal Conditioning for Pulsed-Current Synchronous Measurements.

This paper describes a compact electronic system employing a synchronous demodulation measurement method for the acquisition of pulsed-current signals. The fabricated prototype shows superior performance in terms of signal-to-noise ratio in comparison to conventional instrumentation performing free-running measurements, especially when extremely narrow pulses are concerned. It shows a reading error around 0.1% independently of the signal duty cycle (D) in the investigated D = 10−4−10−3 range. Conversely, high-precision electrometers display reading errors as high as 30% for a D = 10−4, which reduces to less than 1% only for D > 3 × 10−3. Field tests demonstrate that the developed front-end/readout electronics is particularly effective when coupled to dosimeters irradiated with the X-rays sourced by a medical linear accelerator. Therefore, it may surely be exploited for the real-time monitoring of the dosimeter output current, as required in modern radiotherapy techniques employing ultra-narrow pulses of high-energy photons or nuclear particles.

Factors associated with adverse COVID-19 outcomes in patients with psoriasis-insights from a global registry-based study.

BACKGROUND: The multimorbid burden and use of systemic immunosuppressants in people with psoriasis may confer greater risk of adverse outcomes of coronavirus disease 2019 (COVID-19), but the data are limited. OBJECTIVE: Our aim was to characterize the course of COVID-19 in patients with psoriasis and identify factors associated with hospitalization. METHODS: Clinicians reported patients with psoriasis with confirmed/suspected COVID-19 via an international registry, Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection. Multiple logistic regression was used to assess the association between clinical and/or demographic characteristics and hospitalization. A separate patient-facing registry characterized risk-mitigating behaviors. RESULTS: Of 374 clinician-reported patients from 25 countries, 71% were receiving a biologic, 18% were receiving a nonbiologic, and 10% were not receiving any systemic treatment for psoriasis. In all, 348 patients (93%) were fully recovered from COVID-19, 77 (21%) were hospitalized, and 9 (2%) died. Increased hospitalization risk was associated with older age (multivariable-adjusted odds ratio [OR] = 1.59 per 10 years; 95% CI = 1.19-2.13), male sex (OR = 2.51; 95% CI = 1.23-5.12), nonwhite ethnicity (OR = 3.15; 95% CI = 1.24-8.03), and comorbid chronic lung disease (OR = 3.87; 95% CI = 1.52-9.83). Hospitalization was more frequent in patients using nonbiologic systemic therapy than in those using biologics (OR = 2.84; 95% CI = 1.31-6.18). No significant differences were found between classes of biologics. Independent patient-reported data (n = 1626 across 48 countries) suggested lower levels of social isolation in individuals receiving nonbiologic systemic therapy than in those receiving biologics (OR = 0.68; 95% CI = 0.50-0.94). CONCLUSION: In this international case series of patients with moderate-to-severe psoriasis, biologic use was associated with lower risk of COVID-19-related hospitalization than with use of nonbiologic systemic therapies; however, further investigation is warranted on account of potential selection bias and unmeasured confounding. Established risk factors (being older, being male, being of nonwhite ethnicity, and having comorbidities) were associated with higher hospitalization rates.

Proteomic Analysis of HCC-1954 and MCF-7 Cell Lines Highlights Crosstalk between αv and ß1 Integrins, E-Cadherin and HER-2.

Overexpression of human epidermal growth factor receptor-2 (HER-2) occurs in 20% of all breast cancer subtypes, especially those that present the worst prognostic outcome through a very invasive and aggressive tumour. HCC-1954 (HER-2+) is a highly invasive, metastatic cell line, whereas MCF-7 is mildly aggressive and non-invasive. We investigated membrane proteins from both cell lines that could have a pivotal biological significance in metastasis. Membrane protein enrichment for HCC-1954 and MCF-7 proteomic analysis was performed. The samples were analysed and quantified by mass spectrometry. High abundance membrane proteins were confirmed by Western blot, immunofluorescence, and flow cytometry. Protein interaction prediction and correlations with the Cancer Genome Atlas (TCGA) patient data were conducted by bioinformatic analysis. In addition, ß1 integrin expression was analysed by Western blot in cells upon trastuzumab treatment. The comparison between HCC-1954 and MCF-7 membrane-enriched proteins revealed that proteins involved in cytoskeleton organisation, such as HER-2, αv and ß1 integrins, E-cadherin, and CD166 were more abundant in HCC-1954. ß1 integrin membrane expression was higher in the HCC-1954 cell line resistant after trastuzumab treatment. TCGA data analysis showed a trend toward a positive correlation between HER-2 and ß1 integrin in HER-2+ breast cancer patients. Differences in protein profile and abundance reflected distinctive capabilities for aggressiveness and invasiveness between HCC-1954 and MCF-7 cell line phenotypes. The higher membrane ß1 integrin expression after trastuzumab treatment in the HCC-1954 cell line emphasised the need for investigating the contribution of ß1 integrin modulation and its effect on the mechanism of trastuzumab resistance.