Effects of lung volume reduction surgery for emphysema on glycolipidic hormones

BACKGROUND: Pulmonary emphysema is associated with cachexia and disregulation of the hormones regulating the glycolipid metabolism, insulin resistance, and altered substrate utilization. This study aimed at identifying the effects of lung volume reduction surgery (LVRS) on glycolipidic hormones compared to respiratory rehabilitation (RR). METHODS: Thirty-three patients with moderate-to-severe emphysema who were undergoing video-assisted thoracoscopic LVRS were compared to 31 similar patients who refused the operation and followed a standardized RR program. All patients were evaluated before and 12 months after treatment for respiratory function, body composition, glycolipidic hormones, metabolic parameters, and insulin resistance, which was calculated using the homeostatic model assessment index for insulin resistance (HOMA-IR). These groups were compared to a matched healthy control population. RESULTS: Only after LVRS significant improvements were obtained in respiratory function (FEV1, +25.2%; p<0.0001; residual volume, -19.5%; p<0.0001), metabolic parameters (total cholesterol, +13.1%; p<0.01; high-density lipoprotein cholesterol, +11.2%; p<0.01; triglycerides, +18.4; p<0.001; nonesterified fatty acid, -19.7%; p<0.001), and body composition (fat-free mass [FFM], +6.5%; p<0.01; fat mass [FM], +11.9%; p<0.01). The leptin/FM ratio (-6.1%; p<0.01) and resistin/FM ratio (-5.6%; p<0.01) decreased, whereas the adiponectin/FM ratio (+6.9%; p<0.01) and ghrelin (+9.2%; p<0.01) increased, together with reductions in glycemia (-8.8%; p<0.01), insulin level (-20.4%; p<0.001), and HOMA-IR (-27.2%; p<0.0001). The decrement in residual volume was correlated with increment of FFM (rho=-0.49; p<0.02), FM (rho=-0.55; p<0.009), and ghrelin (rho=-0.52; p<0.01), and also with decreases in leptin corrected for FM (rho=0.50; p<0.02) and, marginally, HOMA-IR (rho=0.35; p=0.07). CONCLUSIONS: After LVRS, glycolipidic hormone levels and nutritional status significantly improved, along with insulin resistance reduction and more physiologic utilization of substrates. Correlations between residual volume and body composition as well as glycolipidic hormone levels suggest that postoperative recovery in respiratory dynamics may induce favorable clinical changes when compared to RR

Tidal capture of stars by supermassive black holes: implications for periodic nuclear transients and quasi-periodic eruptions

Stars that plunge into the centre of a galaxy are tidally perturbed by a supermassive black hole (SMBH), with closer encounters resulting in larger perturbations. Exciting these tides comes at the expense of the star’s orbital energy, which leads to the naive conclusion that a smaller pericentre (i.e. a closer encounter between the star and SMBH) always yields a more tightly bound star to the SMBH. However, once the pericentre distance is small enough that the star is partially disrupted, morphological asymmetries in the mass lost by the star can yield an increase in the orbital energy of the surviving core, resulting in its ejection – not capture – by the SMBH. Using smoothed particle hydrodynamics simulations, we show that the combination of these two effects – tidal excitation and asymmetric mass-loss – results in a maximum amount of energy lost through tides of ∼2.5 per cent of the binding energy of the star, which is significantly smaller than the theoretical maximum of the total stellar binding energy. This result implies that stars that are repeatedly partially disrupted by SMBHs many (≳10) times on short-period orbits (≲few years), as has been invoked to explain the periodic nuclear transient ASASSN-14ko and quasi-periodic eruptions, must be bound to the SMBH through a mechanism other than tidal capture, such as a dynamical exchange (i.e. Hills capture)

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Using the Hills Mechanism to Generate Repeating Partial Tidal Disruption Events and ASASSN-14ko

Periodic nuclear transients have been detected with increasing frequency, with one such system -- ASASSN-14ko -- exhibiting highly regular outbursts on a timescale of $114 \pm 1$ days. It has been postulated that the outbursts from this source are generated by the repeated partial disruption of a star, but how the star was placed onto such a tightly bound orbit about the supermassive black hole remains unclear. Here we use analytic arguments and three-body integrations to demonstrate that the Hills mechanism, where a binary system is destroyed by the tides of the black hole, can lead to the capture of a star on a $\sim 114$ day orbit and with a pericenter distance that is comparable to the tidal radius of one of the stars within the binary. Thus, Hills capture can produce stars on tightly bound orbits that undergo repeated partial disruption, leading to a viable mechanism for generating not only the outbursts detected from ASASSN-14ko, but for periodic nuclear transients in general. We also show that the rate of change of the period of the captured star due to gravitational-wave emission is likely too small to produce the observed value for ASASSN-14ko, indicating that in this system there must be additional effects that contribute to the decay of the orbit. In general, however, gravitational-wave emission can be important for limiting the lifetimes of these systems, and could produce observable period decay rates in future events.Comment: 6 pages, 1 figure, and 1 table. Resubmitted to ApJL following first referee repor

The Eccentric Nature of Eccentric Tidal Disruption Events

Upon entering the tidal sphere of a supermassive black hole, a star is ripped apart by tides and transformed into a stream of debris. The ultimate fate of that debris, and the properties of the bright flare that is produced and observed, depends on a number of parameters, including the energy of the center of mass of the original star. Here we present the results of a set of smoothed particle hydrodynamics simulations in which a 1M o˙, γ = 5/3 polytrope is disrupted by a 106 M o˙ supermassive black hole. Each simulation has a pericenter distance of r p = r t (i.e., β ≡ r t/r p = 1 with r t the tidal radius), and we vary the eccentricity e of the stellar orbit from e = 0.8 up to e = 1.20 and study the nature of the fallback of debris onto the black hole and the long-term fate of the unbound material. For simulations with eccentricities e ≲ 0.98, the fallback curve has a distinct, three-peak structure that is induced by self-gravity. For simulations with eccentricities e ⪆ 1.06, the core of the disrupted star reforms following its initial disruption. Our results have implications for, e.g., tidal disruption events produced by supermassive black hole binaries

A retrospective, real-life analysis of metronomic oral single-agent cyclophosphamide for the treatment of platinum-pretreated advanced ovarian carcinoma in Italy

Introduction: Metronomic oral cyclophosphamide (MOC) presents many potential advantages, such as significantly less severe side effects than standard regimens, ease of administration, and the delivery of a dose-dense but not necessarily dose-intense treatment. These observations prompted us to evaluate in a retrospective, multicenter study the efficacy and toxicity of MOC in a real-life series of pretreated cancer patients. Methods: The study is a multicenter, retrospective analysis of the activity of single-agent MOC in patients with recurrent or residual epithelial ovarian, fallopian tube, or primary. Eligible patients were continuously treated with MOC at 50 mg/day until progression, toxicity, or death. Overall response rate (ORR), stable disease (SD), and disease control rate (DCR) were reported. Results: The study included 62 patients. Three patients reached a complete response rate (5%), 11 had a partial response rate (18), and 15 had stabilization of disease (24) for an ORR of 23% and a DCR of 47%. Patients with low-grade indolent tumors showed an ORR and an SD rate higher than that observed in non-indolent ones (33% vs. 18% and 28% vs. 14%, respectively). Overall, progression-free survival was 3.5 months (range 1–9 months). Conclusion: Single-agent MOC is active and very well tolerated in a significant fraction of patients with refractory, recurrent, or residual epithelial ovarian, fallopian tube, or primary peritoneal cancer. In the vision of a practical approach, single-agent MOC may be a useful palliative treatment option for patients with poor tolerance to high-dose regimens or widely pretreated. Further studies are needed better to characterize the role of such an approach in clinical practice