Theory of Rayleigh-Brillouin optical activity light scattering applicable to chiral liquids.

It has long been understood that dilute samples of chiral molecules such as rarefied gases should exhibit Rayleigh optical activity. We extend the existing theory by accounting for molecular dynamics and correlations, thus obtaining a more general theory of Rayleigh-Brillouin optical activity applicable to dense samples such as neat liquids.

Double lumen endobronchial tube intubation: lessons learned from anatomy.

BACKGROUND: Double lumen endobronchial tubes (DLTs) are frequently used to employ single lung ventilation strategies during thoracic surgical procedures. Placement of these tubes can be challenging even for experienced clinicians. We hypothesized that airway anatomy, particularly of the glottis and proximal trachea, significantly impacts the ease or difficulty in placement of these tubes. METHODS: Images from 24 randomly selected Positron Emission Tomography - Computed Tomography (PET-CT) scans were evaluated for several anatomic aspects of the upper airway, including size and angulation of the glottis and proximal tracheal using calibrated CT measurements and an online digital protractor. The anatomic issues identified were confirmed in cadaveric anatomic models. RESULTS: Proximal tracheal diameter measurements in PET-CT scans demonstrated a mean ± standard deviation of 20.4 ± 2.5 mm in 12 males and 15.5 ± 0.98 mm in 12 females (p < 0.001), and both were large enough to accommodate 39 French and 37 French DLTs in males and females, respectively. Subsequent measurements of the posterior angulation of the proximal trachea revealed a mean angle of 40.8 ± 5.7 degrees with no sex differences. By combining the 24 individual posterior tracheal angles with the 16 angled distal tip measurements DLTs (mean angle 24.9 ± 2.1 degrees), we created a series of 384 patient intubation angle scenarios. This data clearly showed that DLT rotation to a full 180 degrees decreased the mean intubation angle between the DLT and the proximal trachea from a mean of 66.6 ± 5.9 to only 15.8 ± 5.9 degrees. CONCLUSIONS: Rotation of DLTs a full 180 instead of the recommended 90 degrees facilitates DLT intubations.

EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study.

BACKGROUND: Treatment options for malignant pleural mesothelioma are scarce. Tazemetostat, a selective oral enhancer of zeste homolog 2 (EZH2) inhibitor, has shown antitumour activity in several haematological cancers and solid tumours. We aimed to evaluate the anti-tumour activity and safety of tazemetostat in patients with measurable relapsed or refractory malignant pleural mesothelioma. METHODS: We conducted an open-label, single-arm phase 2 study at 16 hospitals in France, the UK, and the USA. Eligible patients were aged 18 years or older with malignant pleural mesothelioma of any histology that was relapsed or refractory after treatment with at least one pemetrexed-containing regimen, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of greater than 3 months. In part 1 of the study, participants received oral tazemetostat 800 mg once on day 1 and then twice daily from day 2 onwards. In part 2, participants received oral tazemetostat 800 mg twice daily starting on day 1 of cycle 1, using a two-stage Green-Dahlberg design. Tazemetostat was administered in 21-day cycles for approximately 17 cycles. The primary endpoint of part 1 was the pharmacokinetics of tazemetostat and its metabolite at day 15 after administration of 800 mg tazemetostat, as measured by maximum serum concentration (Cmax), time to Cmax (Tmax), area under the concentration-time curve (AUC) to day 15 (AUC0-t), area under the curve from time 0 extrapolated to infinity (AUC0-∞), and the half-life (t1/2) of tazemetostat, assessed in all patients enrolled in part 1. The primary endpoint of part 2 was the disease control rate (the proportion of patients with a complete response, partial response, or stable disease) at week 12 in patients with malignant pleural mesothelioma per protocol with BAP1 inactivation determined by immunohistochemistry. The safety population included all the patients who had at least one post-dose safety assessment. This trial is now complete and is registered with ClinicalTrials.gov, NCT02860286. FINDINGS: Between July 29, 2016, and June 2, 2017, 74 patients were enrolled (13 in part 1 and 61 in part 2) and received tazemetostat, 73 (99%) of whom had BAP1-inactivated tumours. In part 1, following repeat dosing of tazemetostat at steady state, on day 15 of cycle 1, the mean Cmax was 829 ng/mL (coefficient of variation 56·3%), median Tmax was 2 h (range 1-4), mean AUC0-twas 3310 h·ng/mL (coefficient of variation 50·4%), mean AUC0-∞ was 3180 h·ng/mL (46·6%), and the geometric mean t1/2 was 3·1 h (13·9%). After a median follow-up of 35·9 weeks (IQR 20·6-85·9), the disease control rate in part 2 in patients with BAP1-inactivated malignant pleural mesothelioma was 54% (95% CI 42-67; 33 of 61 patients) at week 12. No patients had a confirmed complete response. Two patients had a confirmed partial response: one had an ongoing partial response with a duration of 18 weeks and the other had a duration of 42 weeks. The most common grade 3-4 treatment-emergent adverse events were hyperglycaemia (five [7%] patients), hyponatraemia (five [7%]), and anaemia (four [5%]); serious adverse events were reported in 25 (34%) of 74 patients. Five (7%) of 74 patients died while on study; no treatment-related deaths occurred. INTERPRETATION: Further refinement of biomarkers for tazemetostat activity in malignant pleural mesothelioma beyond BAP1 inactivation could help identify a subset of tumours that are most likely to derive prolonged benefit or shrinkage from this therapy. FUNDING: Epizyme.

Two new pseudocryptic species in the medium-sized common European land snails, Fruticicola Held, 1838; as a result of phylogeographic analysis of Fruticicola fruticum (O. F. Müller, 1774) (Gastropoda: Helicoidea: Camaenidae).

Fruticicola fruticum (O. F. Müller, 1774), a medium-sized helicoid snail in the Camaenidae, has a wide range in Europe, reaching from the Urals and the Caucasus to the Balkans, and from the southern part of Scandinavia, through Central Europe to eastern and central France and northern Italy. There are numerous studies on its distribution, biology, life cycle, etc., but little is known about the genetic diversity of this taxon. Here, we studied the phylogeny and phylogeography of F. fruticum using two mitochondrial markers: cytochrome oxidase subunit I (COI) and 16S ribosomal RNA (16S); and four nuclear markers: 18S ribosomal RNA (18S), 28S ribosomal RNA (28S), internal transcribed spacer (ITS-2), and histone 3 (H3). The study was based on 59 populations sampled across the range. Whereas nuclear markers showed little differentiation, phylogenetic analysis of COI sequences clearly confirmed the distinctness of the European Fruticicola and Asian Bradybaena (p-distance 0.229). Within Fruticicola 54 haplotypes were detected, haplotype diversity (Hd) = 0.973 ± 0.006, nucleotide diversity (π) = 0.137 ± 0.005. ABGD and PTP delimitation analyzes distinguished eight mOTUs. Two sequences (our mOTU C) from Russia were published in the GenBank as two distinct species: F. schrenckii and F. transbaicalia. Seven further mOTUs identified in our study formed three distinct lineages, regarded as species. The first (mOTU A and mOTU B), represented by 40 populations, occupies a wide range across northern and central Europe, extending east to Ukraine and south to northern Croatia (mOTU B). It encompasses the type locality of F. fruticum, and can be recognized as F. fruticum sensu stricto. Another lineage (mOTU D and mOTU E), represented by six populations in central Romania, appears to form another species. Both mOTUs were found together in one population. A third lineage, containing mOTUs F, G and H, represented by 14 populations, was distributed across the Balkans from N.E. Croatia to Bulgaria. p-distances between the three species ranged from 0.172 to 0.219, and between all the mOTUs, pooled together, from 0.172 to 0.258. The highest genetic diversity was found in species 3 (0.112) and the lowest in species 1 (0.025), despite its largest geographic distribution. Pairwise p-distances, Tamura 3-parameter distances, composite likelihood distances, as well as the coancestry coefficient FST, calculated for all populations pooled together were significantly associated with geographic distance, but this was not the case within each of these three species. The significant association for all populations reflected high diversity between the species coupled with high geographic distances between their populations, not the character of intraspecies diversity. With a few exceptions, there hold a rather infinite island model with low migration. AMOVA detected 78% of the variance between the three species, 18% among populations within the species, and only 3.6% within the populations. The low genetic diversity of widespread F. fruticum s. stricto, compared with much higher diversity of two narrowly distributed newly found species of Fruticicola, may reflect the rapid spread of the former into previously uninhabitable regions, while the latter were able to maintain populations in glacial refugia. The estimated time of divergence between the three species, 1.7-2.19 mya, suggests their ancestors' isolation in southern European refugia during the lower Pleistocene, the Gelasian/Calabrian. There was no clear association of variation in shell morphology and lineage or mOTU identity; on external characters, these species are semicryptic, subtle differences in reproductive anatomy among them were found.

Toroidal Flux Loss due to Flux Emergence Explains why Solar Cycles Rise Differently but Decay in a Similar Way.

A striking feature of the solar cycle is that at the beginning, sunspots appear around midlatitudes, and over time the latitudes of emergences migrate toward the equator. The maximum level of activity (e.g., sunspot number) varies from cycle to cycle. For strong cycles, the activity begins early and at higher latitudes with wider sunspot distributions than for weak cycles. The activity and the width of sunspot belts increase rapidly and begin to decline when the belts are still at high latitudes. Surprisingly, it has been reported that in the late stages of the cycle the level of activity (sunspot number) as well as the widths and centers of the butterfly wings all have the same statistical properties independent of how strong the cycle was during its rise and maximum phases. We have modeled these features using a Babcock-Leighton type dynamo model and show that the flux loss through magnetic buoyancy is an essential nonlinearity in the solar dynamo. Our Letter shows that the nonlinearity is effective if the flux emergence becomes efficient at the mean-field strength of the order of 10^{4} G in the lower part of the convection zone.

Proximal Tubule ß 2-Adrenergic Receptor Mediates Formoterol-Induced Recovery of Mitochondrial and Renal Function after Ischemia-Reperfusion Injury.

Acute kidney injury (AKI) is the rapid loss of renal function after an insult, and renal proximal tubule cells (RPTCs) are central to the pathogenesis of AKI. The ß 2-adrenergic receptor (ß 2AR) agonist formoterol accelerates the recovery of renal function in mice after ischemia-reperfusion injury (IRI) with associated rescue of mitochondrial proteins; however, the cell type responsible for this recovery remains unknown. The role of RPTCs in formoterol-induced recovery of renal function was assessed in a proximal tubule-specific knockout of the ß 2AR (γGT-Cre:ADRB2Flox/Flox). These mice and wild-type controls (ADRB2Flox/Flox) were subjected to renal IRI, followed by once-daily dosing of formoterol beginning 24 hours post-IRI and euthanized at 144 hours. Compared with ADRB2Flox/Flox mice, γGT-Cre:ADRB2Flox/Flox mice had decreased renal cortical mRNA expression of the ß 2AR. After IRI, formoterol treatment restored renal function in ADRB2Flox/Flox but not γGT-Cre:ADRB2Flox/Flox mice as measured by serum creatinine, histopathology, and expression of kidney injury marker-1 (KIM-1). Formoterol-treated ADRB2Flox/Flox mice exhibited recovery of mitochondrial proteins and DNA copy number, whereas γGT-Cre:ADRB2Flox/Flox mice treated with formoterol did not. Analysis of mitochondrial morphology by transmission electron microscopy demonstrated that formoterol increased mitochondrial number and density in ADRB2Flox/Flox mice but not in γGT-Cre:ADRB2Flox/Flox mice. These data demonstrate that proximal tubule ß 2AR regulates renal mitochondrial homeostasis. Formoterol accelerates the recovery of renal function after AKI by activating proximal tubule ß 2AR to induce mitochondrial biogenesis and demonstrates the overall requirement of RPTCs in renal recovery.

Mechanical chiral resolution.

Mechanical interactions of chiral objects with their environment are well-established at the macroscale, like a propeller on a plane or a rudder on a boat. At the colloidal scale and smaller, however, such interactions are often not considered or deemed irrelevant due to Brownian motion. As we will show in this tutorial review, mechanical interactions do have significant effects on chiral objects at all scales, and can be induced using shearing surfaces, collisions with walls or repetitive microstructures, fluid flows, or by applying electrical or optical forces. Achieving chiral resolution by mechanical means is very promising in the field of soft matter and to industry, but has not received much attention so far.

Assessment of Differential Pressures in Chest Drainage Systems: Is What You See What You Get?

BACKGROUND: Dry-suction chest drainage systems are used to achieve proper drainage of the pleural space after cardiothoracic operations. Data on the actual intrapleural pressure during the use of these systems is lacking. The present study was performed to evaluate pressure differences across the circuit using an ex vivo model. METHODS: An ex vivo apparatus coupled to a hospital-grade pleural drainage system was devised to provide calibrated levels of suction and air leak. Simultaneous pressure measurements were obtained at the system outlet and the simulated patient entry site. Trials were conducted with increasing levels of water between the patient and drainage modules at various levels of suction and leak pressures. Signals were recorded at 100 Hz and analyzed using two-way ANOVA. RESULTS: With no obstruction, the drainage system provided precise levels of negative pressure at the patient level (10-40 cm H2O). Addition of fluid in the drainage tubing caused significant differences in transmitted suction (P < 0.001). With increasing air leakage and fluid volume, the pressure differential between the system and patient increased significantly (1.14 to 36.69 cm H2O, P < 0.001). In the off-suction setting, increasing levels of obstruction to 22 cm of water led to development of positive intrapleural pressures (2.6 to 11.1 cm H2O, P < 0.001). CONCLUSIONS: While commercially available chest drainage systems are able to provide predictable levels of suction at the device, intrapleural pressures can be highly variable and depend on complete patency of connecting tubes. Systems capable of modulating the level of suction based on actual intrapleural pressures may enhance recovery after procedures requiring tube thoracotomy.

Percutaneous Cryoablation for the Treatment of Recurrent Malignant Pleural Mesothelioma: Safety, Early-Term Efficacy, and Predictors of Local Recurrence.

PURPOSE: To determine safety and early-term efficacy of CT-guided cryoablation for treatment of recurrent mesothelioma and assess risk factors for local recurrence. MATERIALS AND METHODS: During the period 2008-2012, 24 patients underwent 110 cryoablations for recurrent mesothelioma tumors in 89 sessions. Median patient age was 69 years (range, 48-82 y). Median tumor size was 30 mm (range, 9-113 mm). Complications were graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Recurrence was diagnosed on CT or positron emission tomography/CT by increasing size, nodular enhancement, or hypermetabolic activity and analyzed using the Kaplan-Meier method. Cox proportional hazards model was used to determine covariates associated with local tumor recurrence. RESULTS: Median duration of follow-up was 14.5 months. Complications occurred in 8 of 110 cryoablations (7.3%). All but 1 complication were graded CTCAE v4.0 1 or 2. No procedure-related deaths occurred. Freedom from local recurrence was observed in 100% of cases at 30 days, 92.5% at 6 months, 90.8% at 1 year, 87.3% at 2 years, and 73.7% at 3 years. Tumor recurrence was diagnosed 4.5-24.5 months after cryoablation (mean 5.7 months). Risk of tumor recurrence was associated with a smaller ablative margin from the edge of tumor to iceball ablation margin (multivariate hazard ratio 0.68, CI 0.48-0.95, P = .024). CONCLUSIONS: CT-guided cryoablation is safe for local control of recurrent mesothelioma, with a low rate of complications and promising early-term efficacy. A smaller ablative margin may predispose to tumor recurrence.

Quantitative analysis of mitochondrial morphology and membrane potential in living cells using high-content imaging, machine learning, and morphological binning.

Understanding the processes of mitochondrial dynamics (fission, fusion, biogenesis, and mitophagy) has been hampered by the lack of automated, deterministic methods to measure mitochondrial morphology from microscopic images. A method to quantify mitochondrial morphology and function is presented here using a commercially available automated high-content wide-field fluorescent microscopy platform and R programming-language-based semi-automated data analysis to achieve high throughput morphological categorization (puncta, rod, network, and large & round) and quantification of mitochondrial membrane potential. In conjunction with cellular respirometry to measure mitochondrial respiratory capacity, this method detected that increasing concentrations of toxicants known to directly or indirectly affect mitochondria (t-butyl hydroperoxide [TBHP], rotenone, antimycin A, oligomycin, ouabain, and carbonyl cyanide-p-trifluoromethoxyphenylhydrazone [FCCP]), decreased mitochondrial networked areas in cultured 661w cells to 0.60-0.80 at concentrations that inhibited respiratory capacity to 0.20-0.70 (fold change compared to vehicle). Concomitantly, mitochondrial swelling was increased from 1.4- to 2.3-fold of vehicle as indicated by changes in large & round areas in response to TBHP, oligomycin, or ouabain. Finally, the automated identification of mitochondrial location enabled accurate quantification of mitochondrial membrane potential by measuring intramitochondrial tetramethylrhodamine methyl ester (TMRM) fluorescence intensity. Administration of FCCP depolarized and administration of oligomycin hyperpolarized mitochondria, as evidenced by changes in intramitochondrial TMRM fluorescence intensities to 0.33- or 5.25-fold of vehicle control values, respectively. In summary, this high-content imaging method accurately quantified mitochondrial morphology and membrane potential in hundreds of thousands of cells on a per-cell basis, with sufficient throughput for pharmacological or toxicological evaluation.

Percutaneous cryoablation for the treatment of recurrent thymoma: preliminary safety and efficacy.

Thymoma is the most common primary tumor of the anterior mediastinum and often recurs after initial surgical resection. In this case series, percutaneous cryoablation, a locally ablative technique, was used to treat 25 mediastinal and pleural recurrent thymoma lesions in five patients. Safety and short-term efficacy data were collected. In 23 percutaneous cryoablations (92%), there were no or minimal complications. One serious complication, myasthenia gravis flare, occurred. Over the duration of follow-up (median, 331 d), 18 of 20 ablated lesions (90%) showed no evidence of local recurrence. Percutaneous cryoablation shows promise as a safe and effective treatment modality for recurrent thymoma.

Immunotherapy for malignant pleural mesothelioma. Current status and future prospects.

Malignant pleural mesothelioma (MPM) is a rare malignancy of the pleura that is frequently resistant to conventional therapies. Immunotherapy is a promising investigational approach for MPM that has shown some evidence of clinical benefit in select patients. However, tumor-induced immunosuppression is likely a major impediment to achieving optimal clinical responses to immunotherapeutic intervention. MPM contains a variable degree of infiltrating T-regulatory cells and M2 macrophages, which are believed to facilitate tumor evasion from the host immune system. Additional immunosuppressive factors identified in other human tumor types, such as tumor-associated programmed death ligand-1 expression, may be relevant for investigation in MPM. Conventional cytoreductive therapies, such as radiation, chemotherapy, and surgery, may play a critical role in successful immunotherapeutic strategies by ablating intratumoral and/or systemic immunosuppressive factors, thus creating a host environment more amenable to immunotherapy. This article reviews the immunotherapeutic approaches being evaluated in patients with MPM and discusses how immunotherapy might be rationally combined with conventional tumor cytoreductive therapies for this disease.

Phylogenetic placement, species delimitation, and cyanobiont identity of endangered aquatic Peltigera species (lichen-forming Ascomycota, Lecanoromycetes).

• Premise of this study: Aquatic cyanolichens from the genus Peltigera section Hydrothyriae are subject to anthropogenic threats and, therefore, are considered endangered. In this study we addressed the phylogenetic placement of section Hydrothyriae within Peltigera. We delimited species within the section and identified their symbiotic cyanobacteria.• Methods: Species delimitation and population structure were explored using monophyly as a grouping criterion (RAxML) and Structurama based on three protein-coding genes in combination with two nuclear ribosomal loci. The 16S and rbcLX sequences for the cyanobionts were analyzed in the broad phylogenetic context of free-living and symbiotic cyanobacteria.• Key results: We confirm with high confidence the placement of section Hydrothyriae within the monophyletic genus Peltigera; however, its phylogenetic position within the genus remains unsettled. We recovered three distinct monophyletic groups corresponding to three species: P. hydrothyria, P. gowardii s.s., and P. aquatica Miadl. & Lendemer, the latter being formally introduced here. Each species was associated with an exclusive set of Nostoc haplotypes.• Conclusions: The ITS region alone provides sufficient genetic information to distinguish the three morphologically cryptic species within section Hydrothyriae. Section Hydrothyriae seems to be associated with a monophyletic lineage of Nostoc, that has not been found in symbiotic association with other members of Peltigera. Capsosira lowei should be transferred to the genus Nostoc. Potential threats to P. aquatica should be re-examined based on the recognition of two aquatic species in western North America.

Optical activity in the scattering of structured light.

We observe that optical activity in light scattering can be probed using types of illuminating light other than single plane (or quasi plane) waves and that this introduces new possibilities for the study of molecules and atoms. We demonstrate this explicitly for natural Rayleigh optical activity which, we suggest, could be exploited as a new form of spectroscopy for chiral molecules through the use of illuminating light comprised of two plane waves that are counter propagating.

Diffraction gratings for chiral molecules and their applications.

We suggest the use of certain readily producible types of light to exert a force that points in opposite directions for the enantiomers of a chiral molecule and propose multiple devices based upon this novel manifestation of optical activity: in particular, our discriminatory chiral diffraction grating; a device that could be employed, for example, to measure the enantiomeric excess of a sample of chiral molecules simply and to high precision. Our work is relevant for many types of molecules and our proposed devices may be realizable using currently existing technology.

Geographical and environmental patterns of Carpathian land snail faunas in a region of high endemicity.

The land snail faunas of limestone gorges of Romanian Carpathians were sampled to test the effect of geographic and environmental factors on the malacofauna richness and composition. A total of 134 sites within 28 limestone gorges were surveyed during 2011-2019 using a combined strategy of visual search and litter/topsoil analysis. Environmental variables such as geographic location, altitude, climate, microhabitat type, dominant vegetation, tree cover and width of the gorge were recorded to detect the relationship with species richness and composition. While the numbers of species, their identities and their abundance varied greatly among samples, both presence and absence data and quantitative multivariate analyses showed that region and climate or altitude (both strongly associated with region) accounted for far more variation than differences in tree cover and dominant microhabitat. Nevertheless, the effects of different habitat preferences were evident. The mixture of species with very restricted ranges within this Pleistocene refugium and those that have spread widely during the Holocene raise questions about the meaning of region when related to local richness and composition.

The Sun's differential rotation is controlled by high-latitude baroclinically unstable inertial modes.

Rapidly rotating fluids have a rotation profile that depends only on the distance from the rotation axis, in accordance with the Taylor-Proudman theorem. Although the Sun was expected to be such a body, helioseismology showed that the rotation rate in the convection zone is closer to constant on radii. It has been postulated that this deviation is due to the poles being warmer than the equator by a few degrees. Using numerical simulations, we show that the pole-to-equator temperature difference cannot exceed 7 kelvin as a result of the back-reaction of the high-latitude baroclinically unstable inertial modes. The observed amplitudes of the modes further indicate that this maximum temperature difference is reached in the Sun. We conclude that the Sun's latitudinal differential rotation reaches its maximum allowed value.

Pathophysiology and Management of Chest Wall Pain after Surgical and Non-Surgical Local Therapies for Lung Cancer.

Chest wall pain syndromes can emerge following local therapies for lung cancer and can adversely affect patients' quality-of-life. This can occur after lung surgery, radiation therapy, or percutaneous image-guided thermal ablation. This review describes the multifactorial pathophysiology of chest wall pain syndromes that develop following surgical and non-surgical local therapies for lung cancer and summarizes evidence-based management strategies for inflammatory, neuropathic, myofascial, and osseous pain. It discusses a step-wise approach to treating chest wall pain that begins with non-opioid oral analgesics and includes additional pharmacologic treatments as clinically indicated, such as anticonvulsants, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and various topical treatments. For myofascial pain, physical medicine techniques, such as acupuncture, trigger point injections, deep tissue massage, and intercostal myofascial release can also offer pain relief. For severe or refractory cases, opioid analgesics, intercostal nerve blocks, or intercostal nerve ablations may be indicated. Fortunately, palliation of treatment-related chest wall pain syndromes can be managed by most clinical providers, regardless of the type of local therapy utilized for a patient's lung cancer treatment. In cases where a patient's pain fails to respond to initial medical management, clinicians can consider referring to a pain specialist who can tailor a more specific pharmacologic approach or perform a procedural intervention to relieve pain.

Evaluation of Major Pathologic Response and Pathologic Complete Response as Surrogate End Points for Survival in Randomized Controlled Trials of Neoadjuvant Immune Checkpoint Blockade in Resectable in NSCLC.

INTRODUCTION: Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC. METHODS: A search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were analyzed using a linear regression model weighted by sample size. The regression coefficient and R2 with 95% confidence interval were calculated by the bootstrapping approach. RESULTS: Seven randomized clinical trials were identified for a total of 2385 patients. At the patient level, the R2 of pCR and MPR with 2-year EFS were 0.82 (0.66-0.94) and 0.81 (0.63-0.93), respectively. The OR of 2-year EFS rates by response status was 0.12 (0.07-0.19) and 0.11 (0.05-0.22), respectively. For the 2-year OS, the R2 of pCR and MPR were 0.55 (0.09-0.98) and 0.52 (0.10-0.96), respectively. At the trial level, the R2 for the association of OR for response and HR for EFS was 0.58 (0.00-0.97) and 0.61 (0.00-0.97), respectively. CONCLUSIONS: Our analyses reveal a robust correlation between pCR and MPR with 2-year EFS but not OS. Trial-level surrogacy was moderate but imprecise. More mature follow-up and data to assess the impact of study crossover are needed.

ß2-Adrenoceptor agonists in the regulation of mitochondrial biogenesis.

The stimulation of mitochondrial biogenesis (MB) via cell surface G-protein coupled receptors is a promising strategy for cell repair and regeneration. Here we report the specificity and chemical rationale of a panel of ß2-adrenoceptor agonists with regards to MB. Using primary cultures of renal cells, a diverse panel of ß2-adrenoceptor agonists elicited three distinct phenotypes: full MB, partial MB, and non-MB. Full MB compounds had efficacy in the low nanomolar range and represent two chemical scaffolds containing three distinct chemical clusters. Interestingly, the MB phenotype did not correlate with reported receptor affinity or chemical similarity. Chemical clusters were then subjected to pharmacophore modeling creating two models with unique and distinct features, consisting of five conserved amongst full MB compounds were identified. The two discrete pharmacophore models were coalesced into a consensus pharmacophore with four unique features elucidating the spatial and chemical characteristics required to stimulate MB.