Fazirsiran for Adults with Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA).

BACKGROUND & AIMS: Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT mRNA, reducing deleterious protein synthesis. METHODS: This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25/100/200 mg. The primary endpoint was percentage change in serum Z-AAT concentration from baseline to Week 16. Patients with fibrosis on baseline liver biopsy received treatment on Day 1, Week 4, and then every 12 weeks, and had a second liver biopsy at or after Weeks 48, 72, or 96. Patients without fibrosis received two doses on Day 1 and Week 4. RESULTS: At Week 16, least-squares mean percent declines in serum Z-AAT concentration were -61%, -83% and -94% with fazirsiran 25/100/200 mg, respectively, versus placebo (all P< .0001). Efficacy was sustained through Week 52. At post-dose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histological reduction from baseline in hepatic globule burden. Portal inflammation improved in 5/12 and 0/8 patients with baseline score >0 in the fazirsiran and placebo groups, respectively. Histological METAVIR score improved by >1 point in 7/14 and 3/8 patients with fibrosis >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation and pulmonary function tests remained stable. CONCLUSIONS: Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose dependent manner and reduced hepatic globule burden (NCT03945292).

Clinical and Pathological Features of Osteosarcomas of the Jaws: A Retrospective Study.

INTRODUCTION: Osteosarcomas of the jaw (OSJs) are rare tumors with distinct characteristics from osteosarcomas affecting other bones. This study aims to analyze the clinical, pathological, and therapeutic characteristics of OSJs. METHODS: A retrospective, descriptive cross-sectional study including patients diagnosed with OSJ registered at the "La Paz" University Hospital, Madrid, was performed. RESULTS: Data of eight patients with a diagnosis of OSJ were obtained during the study period of 22 years (2002-2024). The mean age of the patients was 41 years. The distribution was 1:1 between the maxilla and mandible. Painful inflammation was the most frequent clinical manifestation. Conventional osteoblastic osteosarcoma was the most predominant histological type. Survival rate at 5 years was 50%, which decreased to 25% at 10 years. CONCLUSIONS: OSJs differ from conventional osteosarcomas of long tubular bones. Surgery continues to be the mainstay of treatment. However, more studies are needed through which more standardized protocols can be proposed for adjuvant therapeutic management.

Prevalence and Control of Pseudomonas aeruginosa in Tourist Facilities across the Canary Islands, Spain.

Pseudomonas aeruginosa is a common pathogen associated with recreational water facilities and poses risks to public health. However, data on the prevalence of P. aeruginosa in tourist destinations like the Canary Islands, Spain, remain limited. We assessed P. aeruginosa prevalence in 23 tourist facilities from 2016 to 2019. Compliance with water quality standards was evaluated, and 3962 samples were collected and analyzed. We examined different types of recreational water installations, including outer swimming pools, whirlpools, and cold wells. Of the sampled facilities, 31.2% did not comply with the current legislation's parametric values, mainly due to inadequate disinfectant levels, water temperature, and P. aeruginosa presence. The prevalence of P. aeruginosa was 4.8%, comparable to some European countries but lower than others. Cold wells displayed the highest non-compliance rate (89.2%) and yet exhibited a lower P. aeruginosa prevalence (1.9%) than outer swimming pools and whirlpools. Children's presence did not significantly impact P. aeruginosa contamination. Chlorine-based disinfectants are more effective than bromine-based ones in controlling P. aeruginosa. Regional variability in contamination was observed, with Fuerteventura showing lower colonization rates. Disinfectant levels play a critical role in P. aeruginosa control, and maintaining adequate levels is essential, particularly in bromine-treated installations. Our findings provide valuable insights into the prevalence and distribution of P. aeruginosa in recreational waters within tourist facilities. Tailored strategies are needed to ensure water safety in different Spanish regions. Continued monitoring and assessment, combined with artificial intelligence and machine learning, will enable the implementation of targeted interventions to protect the health of recreational water users.

Impacts of a newly formed lava delta on the marine environment: Lava-induced upwelling and abrupt chlorophyll depletion during the Tajogaite eruption (La Palma, 2021).

The 2021 Tajogaite eruption in La Palma (Canary Islands, Spain) emitted vast volumes of lava during 85 days, which reached the ocean in several occasions at the western flank of the island. Most of these flows merged to create a primary lava delta, covering an area of 48 ha, with an additional 30 ha underwater. Here we characterize the effects of the lava-seawater interaction on the surrounding marine environment. The area was sampled during two multidisciplinary oceanographic cruises: the first one comprised the days before the lava reached the ocean and after the first contact; and the second took place a month later, when the lava delta was already formed but still receiving lava inputs. Physical-chemical anomalies were found in the whole water column at different depths up to 300 m in all measured parameters, such as turbidity (+9 NTU), dissolved oxygen concentration (-17.17 µmol kg-1), pHT25 (-0.1), and chlorophyll-a concentration (-0.33 mg m-3). Surface temperature increased up to +2.3 °C (28.5 °C) and surface salinity showed increases and decreases of -1.01 and +0.70, respectively, in a radius of 4 km around the lava delta. In the water column, the heated waters experimented a lava-induced upwelling, bringing deeper, nutrient-rich waters to shallower depths; however, this feature did not trigger any phytoplankton bloom. In fact, integrated chlorophyll-a showed an abrupt decrease of -41 % in just two days and -69 % a month later, compared to prior conditions. The chlorophyll-a depletion reached a distance larger than 2.5 km (not delimited).

Active but not quiescent lupus nephritis during pregnancy is associated with a higher rate of adverse obstetric outcomes: Analysis of a prospective cohort.

OBJECTIVE: To compare the maternal-fetal/neonatal outcome in patients with systemic lupus erythematosus (SLE) with and without lupus nephritis (LN) in remission or with active disease. METHODS: A prospective cohort of pregnant patients with SLE (ACR 1997 criteria) was studied from January 2009 to December 2021. Demographic, clinical, biochemical, and immunological variables as well as the usual maternal-fetal/neonatal complications were recorded. We compared four groups according to the status of SLE during pregnancy: patients with quiescent SLE without lupus nephritis, patients with active SLE without lupus nephritis, patients with quiescent lupus nephritis, and patients with active lupus nephritis. Statistical analysis included descriptive statistics, bivariate analysis, and Cox regression analysis. RESULTS: A total of 439 pregnancies were studied, with a median age of 28 ± 6, SLE duration of 60 months (interquartile range 36-120). A higher frequency of maternal and fetal/neonatal complications was observed in patients with active SLE with or without lupus nephritis. Multivariate analysis showed that active LN was a risk factor for gestational hypertension (hazard ratios [HR] 1.95; 95% confidence intervals [CI]: 1.01-6.39), premature rupture of membranes (HR 3.56; 95% CI: 1.79-16.05) and more frequent cesarean section (HR 1.82; 95% CI: 1.13-2.94). CONCLUSION: LN is associated with a higher frequency of maternal complications, especially in those patients with active disease during pregnancy, and those maternal complications had an impact on poor fetal/neonatal outcomes. Strict control and timely care of LN could improve the obstetric prognosis.

Enhancing Salt Stress Tolerance in Tomato (Solanum lycopersicum L.) through Silicon Application in Roots.

Soil salinization poses a significant threat to agricultural productivity, necessitating innovative agronomic strategies to mitigate its impact. This study focuses on improving salt stress resistance in tomato plants through the application of silicon (Si) in roots. A greenhouse experiment was carried out under normal conditions (control, and 1 and 4 mM Si) and under salinity stress (salt control, and 1 and 4 mM Si). Various parameters were analyzed in leaves and roots. Under normal conditions, tomato plants grown in non-saline conditions exhibited some toxicity when exposed to Na2SiO3. As for the experiments under salt stress conditions, Si mitigated oxidative damage, preserving root cell membrane integrity. The concentration of malondialdehyde was reduced by 69.5%, that of proline was reduced by 56.4% and there was a 57.6% decrease in catalase activity for tomato plants treated with 1 mM Si under salt stress. Furthermore, Fe uptake and distribution, under salt conditions, increased from 91 to 123 mg kg-1, the same concentration as that obtained for the normal control. In all cases, the lower dose produced better results under normal conditions than the 4 mM dose. In summary, this research provides a potential application of Si in non-fertigated crop systems through a radicular pathway.

Impact of Dyslipidemia on Tear Film and Meibomian Gland Dysfunction: A Cross-Sectional Study of the Interplay between Serum Lipid Profile and Ocular Surface Health.

Purpose: To determine the relationship between dyslipidemia and dry eye disease (DED), as well as its influence on tear film and meibomian glands. Methods: This cross-sectional study included 40 patients with a mean age of 35.2 ± 13.9 years without any history of dyslipidemia. DED and serum lipid profile were evaluated after 8 hours of fasting. Patients were classified according to serum lipid levels with the following cut-off values: total cholesterol (TC) (200 mg/dl), high-density lipoprotein (HDL) (40 mg/dl), low-density lipoprotein (LDL) (130 mg/dl), and triglycerides (TG) (150 mg/dl). The relationship between serum lipid levels and DED was analyzed with the following variables: dry eye questionnaire-5 (DEQ-5), first (F-NIBUT) and average (A-NIBUT) noninvasive breakup time, tear meniscus height (TMH), lipid layer grade (LLG), conjunctival bulbar redness (CBR), and upper (U-LAMG) and lower (L-LAMG) loss area of meibomian glands. Results: Regarding tear film, patients with elevated TC and LDL levels reported significantly higher DEQ-5 scores and TMH (P < 0.05), while those with lower HDL levels showed significantly higher LLG (p < 0.05). Regarding MGD, patients with elevated TC, LDL, and TG, as well as lower HDL levels showed significantly higher L-LAMG (p < 0.05). HDL was correlated with LLG (p < 0.05), while TC was correlated with TMH (p < 0.05) and L-LAMG (p < 0.05), respectively. Conclusions: Disorders in TC, HDL, LDL, and TG levels were associated with DED, having an impact on the tear film and meibomian glands, specifically in DEQ-5 scores, LLG, and L-LAMG.

Simulating the cellular context in synthetic datasets for cryo-electron tomography.

Cryo-electron tomography (cryo-ET) allows to visualize the cellular context at macromolecular level. To date, the impossibility of obtaining a reliable ground truth is limiting the application of deep learning-based image processing algorithms in this field. As a consequence, there is a growing demand of realistic synthetic datasets for training deep learning algorithms. In addition, besides assisting the acquisition and interpretation of experimental data, synthetic tomograms are used as reference models for cellular organization analysis from cellular tomograms. Current simulators in cryo-ET focus on reproducing distortions from image acquisition and tomogram reconstruction, however, they can not generate many of the low order features present in cellular tomograms. Here we propose several geometric and organization models to simulate low order cellular structures imaged by cryo-ET. Specifically, clusters of any known cytosolic or membrane bound macromolecules, membranes with different geometries as well as different filamentous structures such as microtubules or actin-like networks. Moreover, we use parametrizable stochastic models to generate a high diversity of geometries and organizations to simulate representative and generalized datasets, including very crowded environments like those observed in native cells. These models have been implemented in a multiplatform open-source Python package, including scripts to generate cryo-tomograms with adjustable sizes and resolutions. In addition, these scripts provide also distortion-free density maps besides the ground truth in different file formats for efficient access and advanced visualization. We show that such a realistic synthetic dataset can be readily used to train generalizable deep learning algorithms.

A Biomimetic Approach to Premyrsinane-Type Diterpenoids: Exploring Microbial Transformation to Enhance Their Chemical Diversity.

Premyrsinane-type diterpenoids have been considered to originate from the cyclization of a suitable 5,6- or 6,17-epoxylathyrane precursor. Their biological activities have not been sufficiently explored to date, so the development of synthetic or microbial approaches for the preparation of new derivatives would be desirable. Epoxyboetirane A (4) is an 6,17-epoxylathyrane isolated from Euphorbia boetica in a large enough amount to be used in semi-synthesis. Transannular cyclization of 4 mediated by Cp2TiIIICl afforded premyrsinane 5 in good yield as an only diasteroisomer. To enhance the structural diversity of premyrsinanes so their potential use in neurodegenerative disorders could be explored, compound 5 was biotransformed by Mucor circinelloides NRRL3631 to give rise to hydroxylated derivatives at non-activated carbons (6-7), all of which were reported here for the first time. The structures and absolute configurations of all compounds were determined through extensive NMR and HRESIMS spectroscopic studies.

Infectious Keratitis: Characterization of Microbial Diversity through Species Richness and Shannon Diversity Index.

Purpose: To characterize microbial keratitis diversity utilizing species richness and Shannon Diversity Index. Methods: Corneal impression membrane was used to collect samples. All swabs were processed and analyzed by Biolab Laboratory (level V-SSN Excellence: ISO 9001:2015), Biolab Srl (Ascoli Piceno, Italy). DNA extraction, library preparation, and sequencing were performed in all samples. After sequencing, low-quality and polyclonal sequences were filtered out by the Ion software. At this point, we employed Kraken2 for microbial community analysis in keratitis samples. Nuclease-free water and all the reagents included in the experiment were used as a negative control. The primary outcome was the reduction in bacterial DNA (microbial load) at T1, expressed as a percentage of the baseline value (T0). Richness and Shannon alpha diversity metrics, along with Bray-Curtis beta diversity values, were calculated using the phyloseq package in R. Principal coordinate analysis was also conducted to interpret these metrics. Results: 19 samples were included in the study. The results exhibited a motley species richness, with the highest recorded value surpassing 800 species. Most of the samples displayed richness values ranging broadly from under 200 to around 600, indicating considerable variability in species count among the keratitis samples. Conclusions: A significant presence of both typical and atypical bacterial phyla in keratitis infections, underlining the complexity of the disease's microbial etiology.

A Set of Multiresistant Isolates of Mycoplasma bovis Subtype ST-1 with a Variable Susceptibility to Quinolones Are Also Circulating in Spain.

Mycoplasma bovis (M. bovis) is one of the worldwide most important infectious agents involved in respiratory complex diseases (RCD). In Spain, the endemic presence of subtypes ST-2 and ST-3 with phenotypic differences linked to their susceptibility to fluoroquinolones opened the way to develop control strategies focused on previous diagnosis of the subtype and the use of directed therapies when M. bovis were involved in RCD. Surprisingly, microbiological studies conducted during 2023 evidenced for the first time the presence of Spanish isolates of a new polC-subtype, previously classified as ST-1, recovered from calves with respiratory symptoms and pneumonia in different areas of the country (n = 16). Curiously, the minimum inhibitory concentration (MIC) to a panel of antimicrobials revealed phenotypic differences between these ST-1 isolates when using fluoroquinolones (FLQ). There is no geographical correlation between MIC profiles even for a set of 8 isolates recovered from different animals in the same flock. Sequencing of 4 genes (gyrA, gyrB, parC and parE) encoding quinolone resistance-determining regions (QRDR) evidenced the presence of accumulate mutations in 2 ST-1 isolates with high FLQ MICs, but not in all them (n = 3), thus suggesting that, as previously recorded for ST-2 isolates, other mechanisms should be involved in the acquisition of resistence to these antimicrobials. Additionally, as previously detected in the Spanish ST-2 and ST-3, subtype ST-1 isolates are also resistant to macrolides or lincosamides.

Resilience and psychological factors among dentistry students who received face-to-face lectures during the COVID-19 pandemic.

BACKGROUND: This research evaluated whether the relationships between factors of resilience, self-esteem, depression, and anxiety in dental students with changes in teaching and learning methods. We also studied the psychological impact of face-to-face lectures during the COVID-19 pandemic. METHODS: This cross-sectional descriptive study used Google Forms to collect data with the Rosenberg Self-Esteem Scale (RSE), Connor-Davidson Risk Resilience Scale (CD-RISC), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI and BDI-II). An open-ended question was also asked about important learning difficulties. RESULTS: The analysis revealed very high levels of resilience (30.23 ± 5.84), self-esteem in the normal range (29.08 ± 4.03), minimal depression levels (12.32 ± 8.05), and low anxiety levels (17.20 ± 12.41). There were no significant differences between sociodemographic variables ranges in regard to all psychological questionnaires. No high levels of depression and anxiety were found. CONCLUSIONS: The levels were low compared to other studies in which online teaching was used, which is explained by the fact that the students retained adequate resilience and self-esteem thanks to being able to contact teachers and, above all, their own peers.

Controlling Coxiella burnetii in naturally infected sheep, goats and cows, and public health implications: a scoping review.

Q fever is a worldwide zoonotic disease which domestic ruminants are the main source of infection for humans. This scoping review summarizes the control measures currently available to reduce Coxiella burnetii (Cb) infection in naturally infected sheep, goat and cattle herds. A total of 28 articles were included in the review. A lack of methodological standardization was noted in the articles analyzed. The results indicated that long-term vaccination in cows reduces bacterial excretion in milk and environmental contamination. In small ruminants, the results of vaccination in terms of efficacy are variable. In goats, there is a reduction in bacterial excretion, unlike in sheep, where a long-term vaccination program is necessary to reduce bacterial excretion. Moreover, the high persistence of viable Cb in the environment means that control measures for sheep are needed for several years. The use of antibiotics as a control measure in cows and sheep was not found to reduce excretion. However, the combination of vaccination with antibiotic therapy appears to have positive effects in small ruminants in terms of controlling outbreaks of Q fever. Hygiene and biosecurity measures are the basic means for controlling Cb infection on ruminant farms and ensuring public health.

Hepatic Diffuse Large B-cell Lymphoma: A Case Report and Review of Literature of Primary Liver Tumors.

Liver tumors rank as the fourth most common cause of cancer. This case report highlights a 45-year-old female patient who presented persistent abdominal pain and no other symptoms. Initially, she was approached with a probable hepatitis of unknown origin, but her condition worsened rapidly. An endoscopic ultrasound was used to characterize the lesion, and a fine needle biopsy of the lesion was performed which revealed a diffuse large B-cell lymphoma that is CD20+ and Ki67+. Hepatic diffuse large B-cell lymphoma, as diagnosed in the patient, is a rare type of lymphoma that arises in the liver. The treatment usually involves chemotherapy, immunotherapy, and radiation therapy. However, the prognosis depends on the stage of the disease and the patient's overall health. This case reinforces the importance of considering hepatic diffuse large B-cell lymphoma in differential diagnosis for primary liver neoplasia.

Improvements in Jump Height, Speed, and Quality of Life through an 8-Week Strength Program in Male Adolescents Soccer Players.

This study aimed to assess the enhancement of physical fitness and quality of life through an 8-week strength training program in male adolescent soccer players aged between 12 and 13 years. A lower body muscle group intervention was performed, with 17 players in the experimental group (EG) and 15 players in the control group (CG). The EG carried out soccer training complemented by specific strength work. Pre- and post- intervention assessments included body composition, jump height, speed with change of direction, maximum speed in 20 m, movement velocity in back-squat, perceived fatigue effort, academic performance, and quality of life. A general linear repeated measures model analysis was used considering each variable, the interaction between groups (EG, CG) and time (basal, 8-week), to analyze the differences between and within groups. The results showed a reduction in fat in the upper limbs and trunk, improvements in jump height, maximum speed of 20 m, and changes of direction, and increased quality of life (p < 0.05) in the EG. It was concluded that a strength program could improve some components of physical performance in male adolescent soccer players.

Factor H-related protein 1 promotes complement-mediated opsonization of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an important human opportunistic pathogen responsible for a wide range of infections. The complement system is the main early host defense mechanism to control these infections. P. aeruginosa counteracts complement attack by binding Factor H (FH), a complement regulator that inactivates C3b, preventing the formation of the C3-convertase and complement amplification on the bacterial surface. Factor H-related proteins (FHRs) are a group of plasma proteins evolutionarily related to FH that have been postulated to interfere in this bacterial mechanism of resisting complement. Here, we show that FHR-1 binds to P. aeruginosa via the outer membrane protein OprG in a lipopolysaccharide (LPS) O antigen-dependent manner. Binding assays with purified components or with FHR-1-deficient serum supplemented with FHR-1 show that FHR-1 competes with FH for binding to P. aeruginosa. Blockage of FH binding to C3b deposited on the bacteria reduces FH-mediated cofactor activity of C3b degradation, increasing the opsonization of the bacteria and the formation of the potent chemoattractant C5a. Overall, our findings indicate that FHR-1 is a host factor that promotes complement activation, facilitating clearance of P. aeruginosa by opsonophagocytosis.

Evaluating GlicoPro Tear Substitute Derived from Helix aspersa Snail Mucus in Alleviating Severe Dry Eye Disease: A First-in-Human Study on Corneal Esthesiometry Recovery and Ocular Pain Relief.

Background: To evaluate the effects of 10% GlicoPro tear substitute therapy in patients with severe dry eye disease (DED). Methods: In this prospective longitudinal study, 30 individuals receiving 10% GlicoPro four times daily for DED were evaluated. The ocular surface disease index (OSDI) questionnaire, average non-invasive break-up time (A-NIBUT), non-anesthetic and anesthetic corneal esthesiometry (CE), ocular pain, and the presence of conjunctivochalasis (CCH) were used as clinical endpoints. Treatment compliance using dosing diaries and AEs was assessed. Results: A significant improvement was observed in the clinical endpoints: the ΔOSDI questionnaire was -39.27 ± 13.22 [-65 to -15] points, ΔA-NIBUT was 3.10 ± 1.31 [1 to 5] s, Δnon-anesthetic CE was 14 ± 6.35 [5 to 25] mm, and Δanesthetic CE was 13 ± 5.35 [5 to 20] mm (p < 0.001 for all comparisons). Ocular pain was reduced in 92.5% of the patients at the end of the follow-up. However, there was no change in the presence of CCH. In addition, all the patients were fully compliant with the dosing and no AEs related to the use of the 10% GlicoPro tear substitute were reported. Conclusions: The 10% GlicoPro tear substitute has the potential to achieve beneficial effects in ocular surface treatments.

An Integrated Process Analysis for Producing Glycerol Carbonate from CO2 and Glycerol.

Glycerol carbonate (GC) is one of the most attractive green chemicals involved in several applications such as polymer synthesis, e. g., the production of polyurethanes and polycarbonates. This relevant chemical can be produced, in a green way, using CO2 (from carbon capture) and glycerol (a byproduct from biodiesel manufacturing). Therefore, in this work, a comprehensive analysis of the GC production process is conducted based on the following synthesis route: urea-dimethyl carbonate-GC using carbon dioxide and glycerol as the main raw materials where the synthesis pathway was efficiently integrated using Aspen Plus. A techno-economic analysis was performed in order to estimate the required capital investment and operating cost for the whole GC process, providing insights on individual capital cost requirements for the urea, dimethyl carbonate, and GC production sections. A total capital cost of $192.1 MM, and a total operating cost of $225.7 MM/y were estimated for the process. The total annualized cost was estimated as $1,558 USD/t of GC produced, competitive with current market price.

Diamond Bur Microblepharoexfoliation Combined with Intense Pulse Light and Meibomian Gland Expression for Evaporative Dry Eye: A Short-term Controlled Clinical Trial.

INTRODUCTION: To assess the efficacy and safety of the combination of microblepharoexfoliation (MBE), intense pulse light (IPL) and meibomian gland expression (MGX) for treatment of meibomian gland dysfunction (MGD). METHODS: This was a prospective, parallel-control trial conducted from April 2022 to January 2023. Participants were assigned to receive either three sessions of MBE-IPL-MGX treatment and home-based therapy (treatment group) or home-based therapy alone (control group). Outcome measures were assessed at baseline and after 2-month follow-up. RESULTS: Seventy eyes of 70 patients were enrolled. MBE-IPL-MGX treatment achieved better improvements than home-based therapy in ocular surface disease index (OSDI) and symptom assessment in dry eye (SANDE) scores, noninvasive tear film break-up time (NIBUT), lipid layer grade (LLG), loss area meibomian gland (LAMG) and meibomian gland yielding secretion score (MGYSS). The mean differences between the two groups were as follows: OSDI (- 11.23 ± 4.68 points, P < 0.001), SANDE (- 24.63 ± 13.41 points, P < 0.001), NIBUT (1.3 ± 1.57 s, P = 0.033), LLG (0.4 ± 0.04 points, P = 0.003), LAMG (- 2.85 ± 1.69%, P = 0.023) and MGYSS (7.5 ± 2.32 points, P < 0.001). In addition, the increment (Δ) of MGYSS after MBE-IPL-MGX treatment was significantly higher in MGD grades 2 and 3 (all P < 0.001). CONCLUSIONS: MBE-IPL-MGX treatment is an effective and well-tolerated procedure that improves dry eye symptoms and signs as well as meibomian gland secretions in patients with MGD. In addition, this treatment is recommended for MGD grades 2 and 3.

Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy.

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity of such aberrant signaling. Although inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of protein phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor-suppressive resistance. Significance: A therapy consisting of deliberate hyperactivation of oncogenic signaling combined with perturbation of the stress responses that result from this is very effective in animal models of colon cancer. Resistance to this therapy is associated with loss of oncogenic signaling and reduced oncogenic capacity, indicative of tumor-suppressive drug resistance.