Intervention for Hepatic and Pulmonary Metastases in Breast Cancer Patients: Prospective, Multi-institutional Registry Study-IMET, Protocol MF 14-02.

BACKGROUND: One fourth of early-stage breast cancer cases become metastatic during the follow-up period. Limited metastasis is a metastatic disease condition in which the number of metastatic sites and the extent of the disease both are limited, and the disease is amenable to metastatic intervention. This prospective study aimed to evaluate intervention for limited metastases in the lung, liver, or both. METHODS: The study enrolled luminal A/B and/or human epidermal growth factor receptor 2 (HER2)-neu+ patients with operable lung and/or liver metastases in the follow-up assessment after completion of primary breast cancer treatment and patients with a diagnosis of metastasis after 2014. Demographic, clinical, tumor-specific, and metastasis detection-free interval (MDFI) data were collected. Bone metastasis in addition to lung and liver metastases also was included in the analysis. The patients were divided into two groups according to the method of treatment for metastases: systemic therapy alone (ST) group or intervention (IT) group. RESULTS: Until June 2020, 200 patients were enrolled in the study. The demographic data were similar between the two groups. The median follow-up time was 77 months (range 55-107 months) in the IT group (n = 119; 59.5%) and 57 months (range 39-84) in the ST-only group (n = 81; 40.5%). The median MDFI was 40 months (range 23-70 months) in the IT group, and 35 months (range 13-61 months) in the ST-only group (p = 0.47). The groups had similar surgeries for the primary tumor and axilla. Most of the patients had liver metastases (49.5%, n = 99), and 42% (n = 84) of the patients had lung metastases. Both lung and liver metastases were found in 8.5% (n = 17) of the patients. The primary tumor was estrogen receptor/progesterone receptor-positive in 75% (n = 150) of the patients, and 32% (n = 64) of the patients had HER2-neu+ tumors. Metastatic-site resection was performed for 32% (n = 64) of the patients, and 27.5% (n = 55) of the patients underwent metastatic ablative interventions. In the Kaplan-Meier survival analysis, the hazard of death (HoD) was 56% lower in the IT group than in the ST-only group (hazard ratio [HR], 0.44; 95% confidence interval [CI] 0.26-0.72; p = 0.001). The HoD was lower in the IT group than in the ST-only group for the patients younger than 55 years (HR, 0.32; 95% CI 0.17-0.62; p = 0.0007). In the multivariable Cox regression model, HoD was significantly lower for the patients who underwent intervention for metastases and had an MDFI longer than 24 months, but their liver metastases doubled the risk of death compared with lung metastases. CONCLUSION: Metastasis-directed interventions have reduced the risk of death for patients with limited lung/liver metastases who are amenable to interventions after completion of primary cancer treatment. For a select group of patients, such as those with luminal A/B or HER2-neu+ breast cancer who are younger than 55 years with limited metastases to the lung and liver or an MDFI longer than 24 months, surgical or ablative therapy for metastases should be considered and discussed on tumor boards.

Plasma membranes are asymmetric in lipid unsaturation, packing and protein shape.

A fundamental feature of cellular plasma membranes (PMs) is an asymmetric lipid distribution between the bilayer leaflets. However, neither the detailed, comprehensive compositions of individual PM leaflets nor how these contribute to structural membrane asymmetries have been defined. We report the distinct lipidomes and biophysical properties of both monolayers in living mammalian PMs. Phospholipid unsaturation is dramatically asymmetric, with the cytoplasmic leaflet being approximately twofold more unsaturated than the exoplasmic leaflet. Atomistic simulations and spectroscopy of leaflet-selective fluorescent probes reveal that the outer PM leaflet is more packed and less diffusive than the inner leaflet, with this biophysical asymmetry maintained in the endocytic system. The structural asymmetry of the PM is reflected in the asymmetric structures of protein transmembrane domains. These structural asymmetries are conserved throughout Eukaryota, suggesting fundamental cellular design principles.

Author Correction: Plasma membranes are asymmetric in lipid unsaturation, packing and protein shape.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Impact of social contacts on SARS-CoV-2 exposure among healthcare workers.

BACKGROUND: Healthcare workers (HCWs) have an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to occupational exposure. Strict measures generally focus on the patient-to-HCW contacts. However, interactions between the HCWs also pose a high risk for SARS-CoV-2 exposure. AIMS: This study was aimed to investigate the effect of social contacts on the level of SARS-CoV-2 exposure risk among workers by broadening the current risk assessment algorithm. METHODS: Contact tracing records of the workers in a large university hospital between 19th March and 31st December 2020 were analysed. Multivariate conditional logistic regression models were estimated to evaluate factors associated with high-risk exposure for contacts among workers. RESULTS: Of the 329 exposed clusters, 260 (79%) were HCW-to-HCW contacted clusters. High-risk exposure was higher in the HCW-to-HCW contacts (44%), when compared to the patient-to-HCW contacts (5%) (P < 0.001). A total of 1827 HCWs contacted a laboratory-confirmed COVID-19-positive co-worker. Among the HCW-to-HCW contacts, high-risk exposure was higher in the support staff (49%, P < 0.001), in non-patient care settings (47%, P < 0.001) and in the social contacts (57%, P < 0.001). Social contacts between workers increased the high-risk exposure (adjusted odds ratio: 3.50, 95% confidence interval 2.62-4.69) in multivariate analysis. CONCLUSIONS: A significant association between social contacts among workers and high-risk exposure of SARS-CoV-2 was observed. The results of the study emphasize the need for policies regarding the improved protection of HCWs in social settings in addition to patient care services.

Secular trends in opportunistic infections, cancers and mortality in patients with AIDS during the era of modern combination antiretroviral therapy.

OBJECTIVES: The aim of the study was to estimate the incidence of, determine risk factors for, and investigate the consequences of opportunistic infections (OIs) and malignancies among patients with the acquired immune deficiency syndrome (AIDS) in the era of modern combination antiretroviral therapy (cART). METHODS: Three enrolment periods (1998-2002, 2003-2005 and 2006-2012), corresponding to changes in predominant cART regimens, were compared among 1889 participants enrolled in a prospective cohort study, the Longitudinal Study of Ocular Complications of AIDS (LSOCA). Incidences of AIDS-related OIs and cancers were estimated. Multivariate logistic and Cox regression models were used to determine the effect of demographic and clinical characteristics on OIs and mortality. RESULTS: Between participants enrolled in the 1998-2002 and 2006-2012 enrolment periods, the incidence of OIs decreased from 27 per 1000 person-years (PY) to 11 per 1000 PY (P < 0.001), and mortality decreased from 41 per 1000 PY to 18 per 1000 PY (P < 0.0001), corresponding to improvements in cART regimens. CONCLUSIONS: Improvements in cART regimens led to a progressive decline in the incidence of OIs and mortality between 1999 and 2013 among patients with AIDS in the era of modern cART.

COVID-19: booster(s) vs. hospitalization and Intensive Care Unit admission.

OBJECTIVE: As the pandemic continues, different vaccine protocols have been implemented to maintain the protection of vaccines and to provide protection against new variants. The aim of this study was to assess hospitalized patients' vaccination status and document the efficacy of boosters. PATIENTS AND METHODS: The patients that were hospitalized due to COVID-19 were enrolled from 28 hospitals in Turkey for five months from September 2021. 5,331 confirmed COVID-19 patients from collaborating centers were randomly enrolled to understand/estimate the distribution of vaccination status in hospitalized patients and to compare the efficacy of vaccination/booster protocols. RESULTS: 2,779 men and 2,552 women of which 2,408 (45.2%) were admitted to Intensive Care Units participated in this study. It was found that the highest risk reduction for all age groups was found in groups that received 4 doses. Four doses of vaccination for every 3.7 people under 50 years of age, for every 5.7 people in the 50-64 age group, and for every 4.3 people over 65 years of age will prevent 1 patient from being admitted to intensive care. Regardless of the type of vaccine, it was found that the risk of ICU hospitalization decreased in those who were vaccinated compared to those who were not vaccinated. Regardless of the type of vaccine, the ICU risk was found to decrease 1.25-fold in those who received 1 or 2 doses of vaccine, 1.18-fold in those who received 3 doses, and 3.26-fold in those who received 4 doses. CONCLUSIONS: The results suggested that the addition of a fourth dose is more effective in preventing intensive unit care even in disadvantaged groups.

Diffusion and interaction dynamics of the cytosolic peroxisomal import receptor PEX5.

Cellular functions rely on proper actions of organelles such as peroxisomes. These organelles rely on the import of proteins from the cytosol. The peroxisomal import receptor PEX5 takes up target proteins in the cytosol and transports them to the peroxisomal matrix. However, its cytosolic molecular interactions have so far not directly been disclosed. Here, we combined advanced optical microscopy and spectroscopy techniques such as fluorescence correlation spectroscopy and stimulated emission depletion microscopy with biochemical tools to present a detailed characterization of the cytosolic diffusion and interaction dynamics of PEX5. Among other features, we highlight a slow diffusion of PEX5, independent of aggregation or target binding, but associated with cytosolic interaction partners via its N-terminal domain. This sheds new light on the functionality of the receptor in the cytosol as well as highlighting the potential of using complementary microscopy tools to decipher molecular interactions in the cytosol by studying their diffusion dynamics.

Self-organizing actin patterns shape membrane architecture but not cell mechanics.

Cell-free studies have demonstrated how collective action of actin-associated proteins can organize actin filaments into dynamic patterns, such as vortices, asters and stars. Using complementary microscopic techniques, we here show evidence of such self-organization of the actin cortex in living HeLa cells. During cell adhesion, an active multistage process naturally leads to pattern transitions from actin vortices over stars into asters. This process is primarily driven by Arp2/3 complex nucleation, but not by myosin motors, which is in contrast to what has been theoretically predicted and observed in vitro. Concomitant measurements of mechanics and plasma membrane fluidity demonstrate that changes in actin patterning alter membrane architecture but occur functionally independent of macroscopic cortex elasticity. Consequently, tuning the activity of the Arp2/3 complex to alter filament assembly may thus be a mechanism allowing cells to adjust their membrane architecture without affecting their macroscopic mechanical properties.

Adaptive evolution of metabolic pathways in Drosophila.

The adaptive significance of enzyme variation has been of central interest in population genetics. Yet, how natural selection operates on enzymes in the larger context of biochemical pathways has not been broadly explored. A basic expectation is that natural selection on metabolic phenotypes will target enzymes that control metabolic flux, but how adaptive variation is distributed among enzymes in metabolic networks is poorly understood. Here, we use population genetic methods to identify enzymes responding to adaptive selection in the pathways of central metabolism in Drosophila melanogaster and Drosophila simulans. We report polymorphism and divergence data for 17 genes that encode enzymes of 5 metabolic pathways that converge at glucose-6-phosphate (G6P). Deviations from neutral expectations were observed at five loci. Of the 10 genes that encode the enzymes of glycolysis, only aldolase (Ald) deviated from neutrality. The other 4 genes that were inconsistent with neutral evolution (glucose-6-phosphate dehydrogenase [G6pd]), phosphoglucomutase [Pgm], trehalose-6-phosphate synthetase [Tps1], and glucose-6phosphatase [G6pase] encode G6P branch point enzymes that catalyze reactions at the entry point to the pentose-phosphate, glycogenic, trehalose synthesis, and gluconeogenic pathways. We reconcile these results with population genetics theory and existing arguments on metabolic regulation and propose that the incidence of adaptive selection in this system is related to the distribution of flux control. The data suggest that adaptive evolution of G6P branch point enzymes may have special significance in metabolic adaptation.

Survey of lead, cadmium, iron, copper and zinc in Kasar cheese.

Lead, cadmium, iron, copper and zinc contents of Kasar cheese sold in the markets of Ankara, Turkey, were determined over 12 months. A total of 240 samples comprising 10 different brands were analysed. Graphite-furnace atomic absorption was employed for the determination of lead and cadmium, and flame atomic absorption for iron, copper and zinc. The mean (range) of the lead, cadmium, iron, copper and zinc content of the samples were 86 (10-421) microg kg(-1), 1.8 (0.3-8.3) microg kg(-1), 4.2 (1.0-14.1) mg kg(-1), 0.7 (0.3-1.6) mg kg(-1) and 37.7 (26.5-63.0) mg kg(-1), respectively. The samples in November, December and January contained higher amounts of lead than those in other months (p < 0.01). Moreover, important differences existed in lead content of the samples between different cheese producers (p < 0.01). The differences in cadmium and iron content of the samples for different months were important (p < 0.01). The iron content of the samples among manufacturers also varied significantly (p < 0.01). However, there were no significant differences in copper and zinc contents of the samples over 12 months (p > 0.05). These findings suggested that some contamination occurred during milk production and/or manufacturing of cheese depending on the equipment used. For a consumption of 100 g Kasar cheese, one would ingest approximately 8.6 microg (4% of the provisional tolerable daily intake, PTDI) of lead, 0.2 microg (0.3%) of cadmium, 0.4 mg (0.9%) of iron, 0.07 mg (2%) of copper and 3.8 mg (6%) of zinc. Therefore, it was concluded that Kasar cheese is not a significant contributor to the intake of investigated heavy metals.