Pigmented acuminated condylomas seborrhoeic keratosis-like: a new entity?

BACKGROUND: Condyloma acuminatum is caused by human papillomavirus (HPV), which typically presents as excrescent, pedunculated, papillomatous lesions which may be of a pale colour. On rare occasions, we have observed pigmented genital lesions that are similar to seborrhoeic keratoses, but with histological findings of condyloma acuminatum and positive genotyping for HPV. We have termed these 'seborrhoeic keratosis-like' type condylomas. METHODS: This is an observational retrospective study. The following clinical data were collected: age, sex, time of evolution, location, isolated or multiple lesions, monomorphous or polymorphous/mixed lesions. HPV genotyping was performed in all cases, and excision for histological study in eight cases. RESULTS: A total of 31 patients were diagnosed with this type of pigmented condylomata acuminata. Of these, 16 had isolated lesions (less than five lesions) and 15 had multiple lesions. 67% of the lesions exhibited slow growth, with an evolution period of greater than 1 year. The most frequent location was the base of the penis and pubis. HPV genotyping of the lesions was positive in all cases, with the HPV-6 genotype predominating (28 cases, 90.3%). The lesions exhibited dermoscopic differences from other pigmented lesions and histological findings attributable to HPV infection (pseudoparakeratosis, koilocytosis, etc) and others similar to those observed in seborrhoeic keratoses. CONCLUSIONS: A total of 31 patients were diagnosed with pigmented verrucous lesions, excrescents, isolated or multiple, in the genital region. These lesions exhibited clinical characteristics similar to seborrhoeic keratoses, with positive genotyping for HPV. In the majority of cases, the genotype was HPV-6. These lesions have been named 'pigmented condylomata acuminata seborrhoeic keratosis-like'. Only 10 cases of these lesions have been described in the literature.

Neuropsychiatric symptoms of patients two years after experiencing severe COVID-19: A mixed observational study.

BACKGROUND: The impact of SARS-CoV-2 infection (COVID-19) on mental health has not been extensively studied in the medium and long term. This study assessed how clinical, biological, and social factors affect mental health in patients who recovered from severe COVID-19. The evaluation was done 90 days after hospital discharge and followed up at 12 and 24 months. METHODS: A retrospective-prospective cohort mixed observational study was conducted on patients over 18 years of age who required hospitalization in Internal Medicine or ICU for severe COVID-19 pneumonia during 2020 and 2021. Demographic information, clinical variables, and data for the scales were obtained from electronic medical records and telephone interviews. For comparisons of the different variables in each clinical variable (insomnia, depression, anxiety), the Student's t-test for independent samples has been used (normal distribution); otherwise, the Mann-Whitney test will be used. All tests and intervals will be performed with a confidence level of 95. Fisher's exact or Pearson's Chi-square test has been used as appropriate for qualitative variables. RESULTS: 201 patients were recruited. 37.3% presented insomnia, 22.4% anxiety, and 21.4% depressive symptoms. A direct association was established between female sex and depressive symptoms. Psychotropic history, fatigue, and C-reactive protein levels (CRP) were correlated with depression. Anosmia and ageusia, CRP, cognitive symptoms, and dyspnea predicted insomnia. Sex, orotracheal intubation (OTI), pain, fatigue, mental health history, and academic level were independent predictors of anxiety. High percentages of depressive, anxiety, and insomnia symptoms were detected in the second month after discharge and persisted at 12 and 24 months. The fatigue variable maintained a significant relationship with depressive symptoms at 2, 12 and 24 months. A possible limitation could be recall bias in retrospective data collection. CONCLUSIONS: This is a novel study to follow up on mental health for two years in patients with severe COVID-19. Clinical, biological, and psychosocial variables could be predictors of depressive symptoms, anxiety, and insomnia. The psychiatric symptoms persisted throughout the 2-year follow-up. These findings are critical for the follow-up of these patients and open the possibility of further studies in the medium and long term.

Characterization of a MHYT domain-coupled transcriptional regulator that responds to carbon monoxide.

The MHYT domain, identified over two decades ago for its potential to detect diatomic gases like CO, O2 or NO, has awaited experimental validation as a protein sensory domain. Here, we characterize the MHYT domain-containing transcriptional regulator CoxC, which governs the expression of the cox genes responsible for aerobic CO oxidation in the carboxidotrophic bacterium Afipia carboxidovorans OM5. The C-terminal LytTR-type DNA-binding domain of CoxC binds to an operator region consisting of three direct repeats sequences overlapping the -35 box at the target PcoxB promoter, which is consistent with the role of CoxC as a specific transcriptional repressor of the cox genes. Notably, the N-terminal transmembrane MHYT domain endows CoxC with the ability to sense CO as an effector molecule, as demonstrated by the relief of CoxC-mediated repression and binding to the PcoxB promoter upon CO exposure. Furthermore, copper serves as the essential divalent cation for the interaction of CO with CoxC, thereby confirming previous hypothesis regarding the role of copper in the gas-sensing mechanism of MHYT domains. CoxC represents the prototype of a novel subfamily of single-component LytTR transcriptional regulators, characterized by the fusion of a DNA-binding domain with a membrane-bound MHYT sensor domain.

Is the invasive Caprella scaura Templeton, 1836 displacing its resident congener Caprella equilibra Say, 1818 in marinas of the South Iberian Peninsula? A long-term spatio-temporal approach.

Although marine invasions are increasingly a matter of concern, the impact of invasive species in the ecosystem and their ability to replace native taxa is still little understood. Data from 2011 to 2021 in marinas of the Southern Iberian Peninsula supported that the invasive amphipod Caprella scaura is replacing the resident Caprella equilibra over time. Six marinas where C. equilibra was abundant in 2011 and C. scaura was absent, are now dominated by C. scaura. Although this displacement is more evident in Mediterranean shores than in Atlantic coasts, it is very variable between marinas. The spreading of the invasive species in marinas of the Alboran Sea mainly occurred from 2011 to 2017, preventing C. equilibra from regaining its former distribution. The ultimate factors responsible for the displacement, such as the aggressive behaviour of C. scaura, environmental influences or physiological performance in a global warming context, should be further investigated experimentally.

Perineural Invasion of Cranial Nerves in Cutaneous Squamous Cell Carcinoma: Unraveling Its Complexities, Diagnostic Challenges, and Multifaceted Treatment Approaches.

Cutaneous squamous cell carcinoma is the second most common neoplasm among non-melanoma skin cancers. When associated with perineural invasion of the cranial nerves, with clinical features often observed in trigeminal and facial nerves due to their cutaneous extension, it may lead to a worse prognosis. This paper introduces a rare case of an 81-year-old male, with a history of a moderately differentiated invasive carcinoma of the left frontal region with perineural invasion on the left trigeminal cranial nerve. The case underscores the aggressive nature of the intraneural infiltration by squamous cell carcinoma and the challenges in managing such advanced malignancies.

Cluster Formation of Self-Assembled Triarylbismuthanes and Charge Transport Characterizations of Gold-Triarylbismuthane-Gold Junctions.

Organometallic molecules are promising for molecular electronic devices due to their potential to improve electrical conductance through access to complex orbital covalency that is not available to light-element organic molecules. However, studies of the formation of organometallic monolayers and their charge transport properties are scarce. Here, we report the cluster formation and charge transport properties of gold-triarylbismuthane-gold molecular junctions. We found that triarylbismuthane molecules with -CN anchoring groups form clusters during the creation of self-assembled submonolayers. This clustering is attributed to strong interactions between the bismuth (Bi) center and the nitrogen atom in the -CN group of adjacent molecules. Examination of the influence of -NH2 and -CN anchoring groups on junction conductance revealed that, despite a stronger binding energy between the -NH2 group and gold, the conductance per molecular unit (i.e., molecule for the -NH2 group and cluster for the -CN group) is higher with the -CN anchoring group. Further analysis showed that an increase in the number of -CN groups from one to three within the junctions leads to a decrease in conductance while increasing the size of the cluster. This demonstrates the significant effects of different anchoring groups and the impact of varying the number of -CN groups on both the charge transport and cluster formation. This study highlights the importance of selecting the appropriate anchoring group in the design of molecular junctions. Additionally, controlling the size and formation of clusters can be a strategic approach to engineering charge transport in molecular junctions.

Neuroprotective compounds alter the expression of genes coding for proteins related to mitochondrial function in activated microglia.

A hallmark of neuroinflammatory disorders is mitochondrial dysfunction. Nevertheless, the transcriptional changes underlying this alteration are not well-defined. Microglia activation, a decrease in mitochondrion biogenesis and a subsequent alteration of the redox are common factors in diseases coursing with neuroinflammation. In the last two decades, components of the adenosinergic system have been proposed as potential therapeutic targets to combat neuroinflammation. In this research, we analyzed by RNAseq the gene expression in activated microglia treated with an adenosine A2A receptor antagonist, SCH 582561, and/or an A3 receptor agonist, 2-Cl-IB-MECA, since these receptors are deeply related to neurodegeneration and inflammation. The analysis was focused on genes related to inflammation and REDOX homeostasis. It was detected that in the three conditions (microglia treated with 2-Cl-IB-MECA, SCH 582561, and the combination) more than 40 % of the detected genes codified by the mitochondrial genome were differentially expressed (FDR < 0.05) (14/34, 16/34, and 13/34) respectively, being almost all of them (>85 %) upregulated in the microglia treated with adenosinergic compounds. Also, we analyzed the differential expression of genes related to mitochondrial function and oxidative stress codified by the nuclear genome. Additionally, we evaluated the oxygen consumption rate (OCR) of mitochondria in microglia treated with LPS and IFN-γ, both alone and in combination with adenosinergic compounds. The data showed an improvement in mitochondrial function with the antagonist of the adenosine A2A receptor, compared to the effects of pro-inflammatory stimulus, confirming a functional effect consistent with the RNAseq data.

Data-driven probabilistic definition of the low energy conformational states of protein residues.

Protein dynamics and related conformational changes are essential for their function but difficult to characterise and interpret. Amino acids in a protein behave according to their local energy landscape, which is determined by their local structural context and environmental conditions. The lowest energy state for a given residue can correspond to sharply defined conformations, e.g. in a stable helix, or can cover a wide range of conformations, e.g. in intrinsically disordered regions. A good definition of such low energy states is therefore important to describe the behaviour of a residue and how it changes with its environment. We propose a data-driven probabilistic definition of six low energy conformational states typically accessible for amino acid residues in proteins. This definition is based on solution NMR information of 1322 proteins through a combined analysis of structure ensembles with interpreted chemical shifts. We further introduce a conformational state variability parameter that captures, based on an ensemble of protein structures from molecular dynamics or other methods, how often a residue moves between these conformational states. The approach enables a different perspective on the local conformational behaviour of proteins that is complementary to their static interpretation from single structure models.

Emerging Spin-Orbit Torques in Low-Dimensional Dirac Materials.

We report a theoretical description of novel spin-orbit torque components emerging in two-dimensional Dirac materials with broken inversion symmetry. In contrast to usual metallic interfaces where fieldlike and dampinglike torque components are competing, we find that an intrinsic dampinglike torque which derives from all Fermi-sea electrons can be simultaneously enhanced along with the fieldlike component. Additionally, hitherto overlooked torque components unique to Dirac materials emerge from the coupling between spin and pseudospin angular momenta, leading to spin-pseudospin entanglement. These torques are found to be resilient to disorder and could enhance the magnetic switching performance of nearby magnets.

Functional states of prelimbic and related circuits during the acquisition of a GO/noGO task in rats.

GO/noGO tasks enable assessing decision-making processes and the ability to suppress a specific action according to the context. Here, rats had to discriminate between 2 visual stimuli (GO or noGO) shown on an iPad screen. The execution (for GO) or nonexecution (for noGO) of the selected action (to touch or not the visual display) were reinforced with food. The main goal was to record and to analyze local field potentials collected from cortical and subcortical structures when the visual stimuli were shown on the touch screen and during the subsequent activities. Rats were implanted with recording electrodes in the prelimbic cortex, primary motor cortex, nucleus accumbens septi, basolateral amygdala, dorsolateral and dorsomedial striatum, hippocampal CA1, and mediodorsal thalamic nucleus. Spectral analyses of the collected data demonstrate that the prelimbic cortex was selectively involved in the cognitive and motivational processing of the learning task but not in the execution of reward-directed behaviors. In addition, the other recorded structures presented specific tendencies to be involved in these 2 types of brain activity in response to the presentation of GO or noGO stimuli. Spectral analyses, spectrograms, and coherence between the recorded brain areas indicate their specific involvement in GO vs. noGO tasks.

Real-time ultrasonic water level IoT sensor for in-situ soil permeability testing.

Soil permeability tests require a time series of water level measurements to determine system losses, including both infiltration and evaporation. Laboratory measurements of flow are standardised by international regulations such as ASTM International, ISO or UNE, but field measurements are not as well described and in some cases may require definition and specification of test conditions. This is the case for geosynthetic clay liner (GCL) products, where permeability is assessed by a laboratory measurement using a flexible wall permeameter as defined in standard test method D 5887-04. This method is not able to evaluate the performance of such products in the field and therefore cannot guarantee their ability to be used for the repair of landfill liner overlays. For this reason, we have defined a field test in a confined steel ring and developed a real-time ultrasonic IoT device to evaluate water losses over a period of time. The test method was applied in Mallorca (Spain) and as a result the quality of a landfill cover repair solution was evaluated, the corresponding civil works were carried out and the basis for future field measurements of soil permeability tests on different materials and conditions was established.

Impact of Pulsatile Machine Perfusion on Posttransplant Recovery in Asystole Donation: Organ Optimization and the Future of Renal Transplantation.

OBJECTIVES: With the increase in life expectancy and the aging of the population, chronic kidney disease has become increasingly prevalent in our environment. Kidney transplantation remains the gold standard treatment for end-stage renal disease, but the supply of renal grafts has not been able to keep pace with growing demand. Because of this rationale, organ selection criteria have been extended (expanded criteria donation), and alternative donation types, such as donation after circulatory death, have been evaluated. These approaches aim to increase the pool of potential donors, albeit with organs of potentially lower quality. Various forms of donations, including donation after circulatory death, have also undergone assessment. This approach aims to augment the pool of potential donors, notwithstanding the compromised quality of organs associated with such methods. Diverse strategies have been explored to enhance graft function, with one of the most promising being the utilization of pulsatile machine perfusion. MATERIALS AND METHODS: We conducted a retrospective analysis on 28 transplant recipients who met the inclusion criterion of sharing the same donor, wherein one organ was preserved by cold storage and the other by pulsatile machine perfusion. We performed statistical analysis on posttransplant recovery parameters throughout the patients' hospitalization, including admission and discharge phases. RESULTS: Statistically significant differences were noted in delayed graft function (P = .04), blood transfusions requirements, and Clavien-Dindo complications. Furthermore, an overall trend of improvement in discharge parameters and hospital stay was in favor of the pulsatile machine perfusion group. CONCLUSIONS: The use of pulsatile machine perfusion as a method of renal preservation results in graft optimization, leading to earlier recovery and fewer complications compared with cold storage in the context of donation after circulatory death.

Targeting calpain-2-mediated junctophilin-2 cleavage delays heart failure progression following myocardial infarction.

Coronary heart disease (CHD) is a prevalent cardiac disease that causes over 370,000 deaths annually in the USA. In CHD, occlusion of a coronary artery causes ischemia of the cardiac muscle, which results in myocardial infarction (MI). Junctophilin-2 (JPH2) is a membrane protein that ensures efficient calcium handling and proper excitation-contraction coupling. Studies have identified loss of JPH2 due to calpain-mediated proteolysis as a key pathogenic event in ischemia-induced heart failure (HF). Our findings show that calpain-2-mediated JPH2 cleavage yields increased levels of a C-terminal cleaved peptide (JPH2-CTP) in patients with ischemic cardiomyopathy and mice with experimental MI. We created a novel knock-in mouse model by removing residues 479-SPAGTPPQ-486 to prevent calpain-2-mediated cleavage at this site. Functional and molecular assessment of cardiac function post-MI in cleavage site deletion (CSD) mice showed preserved cardiac contractility and reduced dilation, reduced JPH2-CTP levels, attenuated adverse remodeling, improved T-tubular structure, and normalized SR Ca2+-handling. Adenovirus mediated calpain-2 knockdown in mice exhibited similar findings. Pulldown of CTP followed by proteomic analysis revealed valosin-containing protein (VCP) and BAG family molecular chaperone regulator 3 (BAG3) as novel binding partners of JPH2. Together, our findings suggest that blocking calpain-2-mediated JPH2 cleavage may be a promising new strategy for delaying the development of HF following MI.

Cmai: Predicting Antigen-Antibody Interactions from Massive Sequencing Data.

The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in various biological contexts. The capability to profile the landscape of antigen-binding affinity of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for profiling antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of the binding between antibodies and antigens that can be scaled to high-throughput sequencing data. Cmai achieved an AUROC of 0.91 in our validation cohort. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data. We found that, during immune-related adverse events (irAEs) caused by immune-checkpoint inhibitor (ICI) treatment, the humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. In contrast, extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of ICI treatment response. Overall, Cmai and our biomarker approach filled in a gap that is not addressed by current antibody optimization works nor works such as AlphaFold3 that predict the structures of complexes of proteins that are known to bind.

Multidisciplinary Experience for Gluteal Fat Grafting.

BACKGROUND: Gluteal fat grafting, colloquially known as Brazilian Butt Lift, has experienced a significant rise in popularity in recent years. Despite this increase, potential complications associated with the procedure have also been observed, necessitating a thorough examination of the current practices and outcomes. METHODS: This study collected experiences of a multidisciplinary group of surgeons through a detailed survey sent in April 2022. This study aimed to shed light on the practices employed by these surgeons, the frequency and types of complications they encounter, and the overall outcomes of their procedures. RESULTS: Of the 100 surgeons surveyed, 86 responded. The study identified that pulmonary fat embolism (PFE) was the most serious complication, with fatality due to PFE recorded at a rate of 1:23,878. Liposuction site seromas were the most common complications, with an overall rate of 2.45%. Although there were no overall differences in complications between plastic and non-plastic surgeons, plastic surgeons were found to have a sixfold increase in the odds of experiencing a liposuction seroma. The survey also revealed substantial practice variations, particularly regarding fat preparation methods, recipient-site preparation, antibiotic use, and postoperative care protocols. CONCLUSION: Despite known complications, a strong tendency to continue performing these procedures was observed among surgeons, demonstrating the sustained demand and acceptance of the procedure. This study underscores the need for continued surveillance and research to enhance the safety and effectiveness of gluteal fat grafts. The experiences and data gathered from practicing surgeons provide valuable insights, paving the way for refining techniques, building consensus, and facilitating informed discussions with patients about the risks and benefits of the procedure. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Post-cardiotomy extracorporeal life support: A cohort of cannulation in the general ward.

OBJECTIVES: Post-cardiotomy extracorporeal life support (ECLS) cannulation might occur in a general post-operative ward due to emergent conditions. Its characteristics have been poorly reported and investigated This study investigates the characteristics and outcomes of adult patients receiving ECLS cannulation in a general post-operative cardiac ward. METHODS: The Post-cardiotomy Extracorporeal Life Support (PELS) is a retrospective (2000-2020), multicenter (34 centers), observational study including adult patients who required ECLS for post-cardiotomy shock. This PELS sub-analysis analyzed patients´ characteristics, in-hospital outcomes, and long-term survival in patients cannulated for veno-arterial ECLS in the general ward, and further compared in-hospital survivors and non-survivors. RESULTS: The PELS study included 2058 patients of whom 39 (1.9%) were cannulated in the general ward. Most patients underwent isolated coronary bypass grafting (CABG, n = 15, 38.5%) or isolated non-CABG operations (n = 20, 51.3%). The main indications to initiate ECLS included cardiac arrest (n = 17, 44.7%) and cardiogenic shock (n = 14, 35.9%). ECLS cannulation occurred after a median time of 4 (2-7) days post-operatively. Most patients' courses were complicated by acute kidney injury (n = 23, 59%), arrhythmias (n = 19, 48.7%), and postoperative bleeding (n = 20, 51.3%). In-hospital mortality was 84.6% (n = 33) with persistent heart failure (n = 11, 28.2%) as the most common cause of death. No peculiar differences were observed between in-hospital survivors and nonsurvivors. CONCLUSIONS: This study demonstrates that ECLS cannulation due to post-cardiotomy emergent adverse events in the general ward is rare, mainly occurring in preoperative low-risk patients and after a postoperative cardiac arrest. High complication rates and low in-hospital survival require further investigations to identify patients at risk for such a complication, optimize resources, enhance intervention, and improve outcomes.

Orthotopic Models Using New, Murine Lung Adenocarcinoma Cell Lines Simulate Human Non-Small Cell Lung Cancer Treated with Immunotherapy.

Understanding tumor-host immune interactions and the mechanisms of lung cancer response to immunotherapy is crucial. Current preclinical models used to study this often fall short of capturing the complexities of human lung cancer and lead to inconclusive results. To bridge the gap, we introduce two new murine monoclonal lung cancer cell lines for use in immunocompetent orthotopic models. We demonstrate how our cell lines exhibit immunohistochemical protein expression (TTF-1, NapA, PD-L1) and common driver mutations (KRAS, p53, and p110α) seen in human lung adenocarcinoma patients, and how our orthotopic models respond to combination immunotherapy in vivo in a way that closely mirrors current clinical outcomes. These new lung adenocarcinoma cell lines provide an invaluable, clinically relevant platform for investigating the intricate dynamics between tumor and the immune system, and thus potentially contributes to a deeper understanding of immunotherapeutic approaches to lung cancer treatment.

A family of Cd(II) coordination polymers constructed from 6-aminopicolinate and bipyridyl co-linkers: study of their growth in paper and photoluminescence sensing of Fe3+ and Zn2+ ions.

In this work, we report on five novel coordination polymers (CPs) based on the linkage of the [Cd(6apic)2] building block [where 6apic = 6-aminopicolinate] by different bipyridine-type organic spacers, forming different coordination compounds with the following formulae: [Cd(µ-6apic)2]n (1), {[Cd(6apic)2(µ-bipy)]·H2O}n (2), {[Cd(6apic)2(µ-bpe)]·2H2O}n (3), [Cd(6apic)(µ-6apic)(µ-bpa)0.5]n (4) and {[Cd2(6apic)4(µ-tmbp)]·7H2O}n (5) [where bipy = 4,4'-bipyridine, bpe = 1,2-di(4-pyridyl)ethylene, bpa = 1,2-di(4-pyridyl)ethane (bpa) and tmbp = 1,3-di(4-pyridyl)propane]. Most of the synthesized compounds form infinite metal-organic rods through the linkage of the building block by the bipyridine-type linker, except in the case of compound 4 whose assembly forms a densely packed 3D architecture. All compounds were fully characterized and their photoluminescence properties were studied experimentally and computationally through density functional theory (DFT) calculations. All compounds display, upon UV excitation, a similar blue emission of variable intensity depending on the linker employed for the connection of the building units, among which compound 2 deserves to be highlighted for its room temperature phosphorescence (RTP) with an emission lifetime of 32 ms that extends to 79 ms at low temperature. These good photoluminescence properties, in addition to its stability in water over a wide pH range (between 2 and 10), motivated us to study compound 2 as a sensor for the detection of metal ions in water, and it showed high sensitivity to Fe3+ through a fluorescence turn-off mechanism and an unspecific turn-on response to Zn2+. Furthermore, the compound is processed as a paper-based analytical device (PAD) in which the phosphorescence emission is preserved, improving the sensing capacity toward Fe3+ ions.

HER2DX Genomic Assay in HER2-positive Early Breast Cancer Treated with Trastuzumab and Pertuzumab: A Correlative Analysis from PHERGain Phase II Trial.

PURPOSE: To assess the predictive capability of HER2DX assay following (neo)adjuvant trastuzumab-pertuzumab (HP)-based therapy in HER2-positive (HER2+) early breast cancer (EBC). EXPERIMENTAL DESIGN: HER2DX was analyzed in baseline pre-treatment tumors from PHERGain trial. Patients with stage I-IIIA HER2+ EBC were randomized to group A (docetaxel, carboplatin, and HP [TCHP]) and group B (HP ± endocrine therapy). PET response was evaluated after 2 cycles. Group A received TCHP for 6 cycles regardless of PET response. Group B continued with HP ± endocrine therapy for 6 cycles (PET-responders) or with TCHP for 6 cycles (PET-non-responders). The primary objective was to associate HER2DX pCR-score with pathological complete response (pCR). The secondary objective was the association of HER2DX risk-score with 3-year invasive disease-free survival (iDFS). RESULTS: HER2DX was performed on 292 (82.0%) tumors. The overall pCR rate was 38.0%, with pCR rates of 56.4% in group A and 33.8% in group B. In multivariable analysis including treatment and clinicopathological factors, HER2DX pCR-score (continuous variable) significantly correlated with pCR (odds ratio [OR]=1.29, 95% confident interval [CI] 1.10-1.54, p<0.001). HER2DX-defined pCR-high, med, and low groups exhibited pCR rates of 50.4%, 35.8%, and 23.2%, respectively (pCR-high vs pCR-low OR=3.27, CI 1.54-7.09, p<0.001). In patients with residual disease, HER2DX high-risk group demonstrated numerically worse 3-year iDFS than the low-risk group (89.8% vs 100%; HR= 2.70, 95% CI 0.60-12.18, p=0.197). CONCLUSIONS: HER2DX predicts pCR in the context of neoadjuvant HP-based therapy, regardless of chemotherapy addition, and might identify patients at higher risk of recurrence among patients with residual disease.

Neuroanatomical dimensions in medication-free individuals with major depressive disorder and treatment response to SSRI antidepressant medications or placebo.

Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Our objective was to identify the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressants or placebo. In the COORDINATE-MDD consortium, raw MRI data were shared from international samples (N = 1,384) of medication-free individuals with first-episode and recurrent MDD (N = 685) in a current depressive episode of at least moderate severity, but not treatment-resistant depression, as well as healthy controls (N = 699). Prospective longitudinal data on treatment response were available for a subset of MDD individuals (N = 359). Treatments were either SSRI antidepressant medication (escitalopram, citalopram, sertraline) or placebo. Multi-center MRI data were harmonized, and HYDRA, a semi-supervised machine-learning clustering algorithm, was utilized to identify patterns in regional brain volumes that are associated with disease. MDD was optimally characterized by two neuroanatomical dimensions that exhibited distinct treatment responses to placebo and SSRI antidepressant medications. Dimension 1 was characterized by preserved gray and white matter (N = 290 MDD), whereas Dimension 2 was characterized by widespread subtle reductions in gray and white matter (N = 395 MDD) relative to healthy controls. Although there were no significant differences in age of onset, years of illness, number of episodes, or duration of current episode between dimensions, there was a significant interaction effect between dimensions and treatment response. Dimension 1 showed a significant improvement in depressive symptoms following treatment with SSRI medication (51.1%) but limited changes following placebo (28.6%). By contrast, Dimension 2 showed comparable improvements to either SSRI (46.9%) or placebo (42.2%) (ß = -18.3, 95% CI (-34.3 to -2.3), P = 0.03). Findings from this case-control study indicate that neuroimaging-based markers can help identify the disease-based dimensions that constitute MDD and predict treatment response.