Measurement of the

The cross section of the ^{13}C(α,n)^{16}O reaction is needed for nuclear astrophysics and applications to a precision of 10% or better, yet inconsistencies among 50 years of experimental studies currently lead to an uncertainty of ≈15%. Using a state-of-the-art neutron detection array, we have performed a high resolution differential cross section study covering a broad energy range. These measurements result in a dramatic improvement in the extrapolation of the cross section to stellar energies potentially reducing the uncertainty to ≈5% and resolving long standing discrepancies in higher energy data.

Dynamically Induced Symmetry Breaking and Out-of-Equilibrium Topology in a 1D Quantum System.

Nontrivial topology in lattices is characterized by invariants-such as the Zak phase for one-dimensional (1D) lattices-derived from wave functions covering the Brillouin zone. We realize the 1D bipartite Rice-Mele (RM) lattice using ultracold ^{87}Rb and focus on lattice configurations possessing various combinations of chiral, time-reversal, and particle-hole symmetries. We quench between configurations and use a form of quantum state tomography, enabled by diabatically tuning lattice parameters, to directly follow the time evolution of the Zak phase as well as a chiral winding number. The Zak phase evolves continuously; however, when chiral symmetry transiently appears in the out-of-equilibrium system, the chiral winding number becomes well defined and can take on any integer value. When quenching between two configurations obeying the same three symmetries, the Zak phase is time independent; we confirm the dynamically induced symmetry breaking predicted in [McGinley and Cooper, Phys. Rev. Lett. 121, 090401 (2018)PRLTAO0031-900710.1103/PhysRevLett.121.090401] that chiral symmetry is periodically restored, at which times the winding number changes by ±2, yielding values that are not present in the native RM Hamiltonian.

Floquet Engineering Topological Dirac Bands.

We experimentally realized a time-periodically modulated 1D lattice for ultracold atoms featuring a pair of linear bands, each with a Floquet winding number. These bands are spin-momentum locked and almost perfectly linear everywhere in the Brillouin zone: a near-ideal realization of the 1D Dirac Hamiltonian. We characterized the Floquet winding number using a form of quantum state tomography, covering the Brillouin zone and following the micromotion through one Floquet period. Last, we altered the modulation timing to lift the topological protection, opening a gap at the Dirac point that grew in proportion to the deviation from the topological configuration.

EVALUATION OF SEXUAL FUNCTION IN TRANSGENDER AND GENDER DIVERSE INDIVIDUALS; A CALL FOR ACTION.

Sexual function is a key factor impacting all individuals' wellbeing, including the transgender and gender diverse (TGGD) population. Lack of validated sexual function evaluation tools for this community contributes to gaps in medical knowledge, barriers to proper assessment, interventions, and an understanding of sexual function expectations pre and post gender-affirming surgery (GAS). Current studies indicate beneficial individualized treatments for management of sexual dysfunction in TGGD individuals, while demonstrating the importance of applicable and validated sexual function assessments. In the evaluation of sexual function for these patients, it is essential to consider the social, mental, and physical components experienced by this community as well as all variations of sexual practices and preferences. Currently, due to the general lack of an index of assessment, providers and/or researchers are left to adapt one of the validated cisgender tools or create non-validated evaluation tools when assessing TGGD patients. Through the creation of unique validated sexual function tools, providers will be able to improve affirming patient care, reduce stigma, and ensure accurate sexual function evaluation.

Doripenem Treatment during Continuous Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa. While the initial dosing recommendation for renally competent patients and patients undergoing continuous renal replacement therapy (cRRT) was 500 mg every 8 h (q8h), the dose for renally competent patients was updated to 1 g q8h in June 2012. There are no updated data for the dosing of patients on continuous renal replacement therapy. The original dosing regimen for cRRT patients was based on nonseptic patients, while newer publications chose comparatively low target concentrations for a carbapenem. Thus, there is an urgent need for updated recommendations for dosing during cRRT. In the trial presented here, we included 13 oliguric septic patients undergoing cRRT in an intensive care setting. Five patients each were treated with hemodiafiltration or hemodialysis, while three patients received hemofiltration treatment. All patients received 1 g doripenem every 8 h. Doripenem concentrations in the plasma and ultrafiltrate were measured over 48 h. The mean hemofilter clearance was 36.53 ml/min, and the mean volume of distribution was 59.26 liters. The steady-state trough levels were found at 8.5 mg/liter, with no considerable accumulation. Based on pharmacokinetic and pharmacodynamic considerations, we propose a regimen of 1 g q8h, which may be combined with a loading dose of 1.5 to 2 g for critically ill patients. (This study has been registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

Evaluation of single-cell biomechanics as potential marker for oral squamous cell carcinomas: a pilot study.

OBJECTIVES: Early detection of oral cancer is a major health issue. The objective of this pilot study was to analyze the deformability of healthy and cancer cells using a microfluidic optical stretcher (OS). MATERIAL AND METHODS: Different cancer cell lines, primary oral cancer cells, and their healthy counterparts were cultivated and characterized, respectively. A measurable deformation of the cells along the optical axis was detected, caused by surface stress, which is optically induced by the laser power. RESULTS: All cells revealed a viscoelastic extension behavior and showed a characteristic deformation response under laser light exposure. The CAL-27/-33 cells exhibited the highest relative deformation. All other cells achieved similar values, but on a lower level. The cytoskeleton reacts sensitively of changing environmental conditions, which may be influenced by growth behavior of the cancer specimens. Nevertheless, the statistical analysis showed significant differences between healthy and cancer cells. CONCLUSION: Generally, malignant and benign cells showed significantly different mechanical behavior. Cancer-related changes influence the composition of the cytoskeleton and thus affect the deformability, but this effect may be superimposed by cell cultivation conditions or cell doubling time. These influences had to be substituted by brush biopsies to minimize confounders in pursuing investigations.

Effect of Treatment of Residual Disease After Immunotherapy-Based Combinations on Complete Response Rate of Patients With Metastatic Renal Cell Carcinomas.

INTRODUCTION: Immune checkpoint inhibitor (ICI)-based combinations have revolutionized the management of first-line metastatic renal cell carcinoma (mRCC) by improving patient survival. Large phase 3 randomized trials assessing ICI-based combinations have reported complete response (CR) rates of 10% to 18% in the first-line setting. However, there is a scarcity of data about the effect of treatment of residual disease regarding CR rates improvement. MATERIALS AND METHODS: We included retrospectively all consecutive mRCC patients treated in first-line setting at the Institut de Cancérologie Strasbourg Europe with an ICI-based combination involving ICI or TKI, either alone or with added local treatment of residual disease. Patients were characterized according to IMDC risk. Radiologic response was defined according to RECIST v1.1. RESULTS: We enrolled 80 mRCC patients treated with ICI-based combinations between May 2015 and May 2022. The median age was 63 years. Regarding IMDC risk, there were 12 favourable (15%), 50 intermediate (63%), and 18 poor-risk (22%) patients. Forty-seven patients (59%) received ICI + ICI, 24 (30%) received ICI + TKI, and 9 (11%) received another ICI-based therapy. In total, 8 achieved CR (10%), 36 patients (45%) achieved partial response, 23 (29%) achieved stable disease and 12 achieved progressive disease (15%) as the best response with systemic therapy alone. By adding local treatment of residual disease, 11 additional patients (14%) achieved radiological NED. Residual disease resected sites included kidney (n = 6), lymph nodes (n = 5), lung metastases (n = 2) and liver metastases (n = 1). CONCLUSIONS: The resection of residual disease after first-line ICI-based therapy is associated with improved CR rate (CR + NED) in patients with mRCC. These results need to be validated in prospective trial. PATIENT SUMMARY: In recent years, the advent of immunotherapy has radically changed the management of patients with metastatic kidney cancer. Approximately 10% to 18% of these patients using immune checkpoint inhibitor (ICI)-based combinations no longer have detectable disease on CT scans (complete response). There are currently few data on the use of treatment of residual disease to increase the number of patients in complete response. In this retrospective study, the complete response rate with ICI-based treatment was 10%. When local treatment was added, the number of patients with a complete response increased to 24%. This strategy could increase the number of patients with a prolonged complete response in the future.

Analysis of multiple physical parameters for mechanical phenotyping of living cells.

Since the cytoskeleton is known to regulate many cell functions, an increasing amount of effort to characterize cells by their mechanical properties has occured. Despite the structural complexity and dynamics of the multicomponent cytoskeleton, mechanical measurements on single cells are often fit to simple models with two to three parameters, and those parameters are recorded and reported. However, different simple models are likely needed to capture the distinct mechanical cell states, and additional parameters may be needed to capture the ability of cells to actively deform. Our new approach is to capture a much larger set of possibly redundant parameters from cells' mechanical measurement using multiple rheological models as well as dynamic deformation and image data. Principal component analysis and network-based approaches are used to group parameters to reduce redundancies and develop robust biomechanical phenotyping. Network representation of parameters allows for visual exploration of cells' complex mechanical system, and highlights unexpected connections between parameters. To demonstrate that our biomechanical phenotyping approach can detect subtle mechanical differences, we used a Microfluidic Optical Cell Stretcher to mechanically stretch circulating human breast tumor cells bearing genetically-engineered alterations in c-src tyrosine kinase activation, which is known to influence reattachment and invasion during metastasis.

Dynamical instability of 3D stationary and traveling planar dark solitons.

Here we revisit the topic of stationary and propagating solitonic excitations in self-repulsive three-dimensional (3D) Bose-Einstein condensates by quantitatively comparing theoretical analysis and associated numerical computations with our experimental results. Motivated by numerous experimental efforts, including our own herein, we use fully 3D numerical simulations to explore the existence, stability, and evolution dynamics of planar dark solitons. This also allows us to examine their instability-induced decay products including solitonic vortices and vortex rings. In the trapped case and with no adjustable parameters, our numerical findings are in correspondence with experimentally observed coherent structures. Without a longitudinal trap, we identify numerically exact traveling solutions and quantify how their transverse destabilization threshold changes as a function of the solitary wave speed.

Creating solitons with controllable and near-zero velocity in Bose-Einstein condensates.

Established techniques for deterministically creating dark solitons in repulsively interacting atomic Bose-Einstein condensates (BECs) can only access a narrow range of soliton velocities. Because velocity affects the stability of individual solitons and the properties of soliton-soliton interactions, this technical limitation has hindered experimental progress. Here we create dark solitons in highly anisotropic cigar-shaped BECs with arbitrary position and velocity by simultaneously engineering the amplitude and phase of the condensate wave function, improving upon previous techniques which explicitly manipulated only the condensate phase. The single dark soliton solution present in true one-dimensional (1D) systems corresponds to the kink soliton in anisotropic three-dimensional systems and is joined by a host of additional dark solitons, including vortex ring and solitonic vortex solutions. We readily create dark solitons with speeds from zero to half the sound speed. The observed soliton oscillation frequency suggests that we imprinted solitonic vortices, which for our cigar-shaped system are the only stable solitons expected for these velocities. Our numerical simulations of 1D BECs show this technique to be equally effective for creating kink solitons when they are stable. We demonstrate the utility of this technique by deterministically colliding dark solitons with domain walls in two-component spinor BECs.

Some epidermolysis bullosa acquisita sera react with epitopes within the triple-helical collagenous domain as indicated by immunoelectron microscopy.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) autoantibodies recognize epitopes predominantly within the N-terminal noncollagenous (NC)-1 domain of type VII collagen. Recently, some EBA cases with reactivity to other domains, i.e. the triple-helical (T-H) collagenous domain and the NC-2 domain, have been reported. OBJECTIVES: To investigate the ultrastructural localization of epitopes for sera from five patients with EBA that were unreactive by immunoblotting with the NC-1, NC-2 and collagenous domains of type VII collagen. METHODS: Immunogold postembedding indirect immunoelectron microscopy was performed using normal human skin and type VII collagen-deficient skin as substrates. RESULTS: Postembedding indirect immunoelectron microscopy revealed that the five EBA sera showed immunoreactivity in the dermis, mainly located 0-400 nm below the lamina densa. IgG labelling was not observed in type VII collagen-deficient skin from a patient with recessive dystrophic epidermolysis bullosa. The distribution histogram found in this study was different from those of sera that reacted with the NC-1 and/or NC-2 domains, and was similar to those of sera reacting with the T-H collagenous domain. CONCLUSIONS: Our results suggest that epitopes within the T-H collagenous domain of type VII collagen are recognized by IgG antibodies from some EBA sera. These antibodies appear to be found in patients with inflammatory-type EBA.

Severe fetal hydrocephalus with and without neural tube defect: a comparative study.

OBJECTIVE: To describe the main perinatal and 1-year outcomes in babies with a prenatal ultrasonographic diagnosis of severe hydrocephalus according to the presence or absence of a neural tube defect (NTD) in a country where abortion is illegal. METHOD: The study population consisted of cases referred to and delivered at Hospital de Clínicas de Porto Alegre, diagnosed between January 1993 and December 2001. The diagnosis of severe hydrocephalus was based on a lateral ventricular atrium diameter > or =15 mm in at least one hemisphere. RESULTS: Sixty cases were ascertained: 28 with NTD (group 1) and 32 without NTD (group 2). The groups were similar in terms of maternal and child variables at birth and hospitalization days during the 1st year of life. The mortality (including intrauterine deaths and deaths of babies with malformations incompatible with life that characterize a very poor prognosis) until 1 year of age was 36% in group 1 and 59% in group 2 (p = 0.077). The rate of cardiac malformations was higher in the group without NTD (p = 0.015). The length of hospital stay after birth (1st admission) was significantly higher in the group with NTD (p = 0.007). CONCLUSIONS: The morbidity was higher in the group with NTD, possibly due to the higher number of surgical interventions in the central nervous system. However, the mortality was higher in the group without NTD, possibly due to the presence of other associated malformations, especially congenital heart disease. Further studies should focus on neurological function and quality of life of the children and their families at the end of the 1st year and after 2 or 6 years of age.

Chp, a homologue of the GTPase Cdc42Hs, activates the JNK pathway and is implicated in reorganizing the actin cytoskeleton.

The p21-activated protein kinases (PAKs) are activated through direct interaction with the GTPases Rac and Cdc42Hs, which are implicated in the control of the mitogen-activated protein kinase (MAP kinase) c-Jun N-terminal kinase (JNK) and the reorganization of the actin cytoskeleton [1-3]. The exact role of the PAK proteins in these signaling pathways is not entirely clear. To elucidate the biological function of Pak2 and to identify its molecular targets, we used a novel two-hybrid system, the Ras recruitment system (RRS), that aims to detect protein-protein interactions at the inner surface of the plasma membrane (described in the accompanying paper by Broder et al. [4]). The Pak2 regulatory domain (PakR) was fused at the carboxyl terminus of a RasL61 mutant protein and screened against a myristoylated rat pituitary cDNA library. Four clones were identified that interact specifically with PakR and three were subsequently shown to encode a previously unknown homologue of the GTPase Cdc42Hs. This approximately 36 kDa protein, designated Chp, exhibits an overall sequence identity to Cdc42Hs of approximately 52%. Chp contains two additional sequences at the amino and carboxyl termini that are not found in any known GTPase. The amino terminus contains a polyproline sequence, typically found in Src homology 3 (SH3)-binding domains, and the carboxyl terminus appears to be important for Pak2 binding. Results from the microinjection of Chp into cells implicated Chp in the induction of lamellipodia and showed that Chp activates the JNK MAP kinase cascade.

Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib-Treated Cancer.

The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-event (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for the individualization of anti-angiogenic therapies.

Characterization of a human endocrine tissue and tumor-associated Ewing's sarcoma antigen.

The histogenesis of Ewing's sarcoma (ES), the second most frequent primary bone tumor in humans, remains controversial. A new cell line (SIM-1) was derived from a peripheral neuroectodermal tumor (PNET) and used for the production of a monoclonal antibody (HBA-71), which recognizes a novel cell surface antigen of ES- and PNET-derived cells and paraffin-embedded tumor sections. The HBA-71 antigen expression is restricted to PNET/ES and the antigen was not detected on cell lines or tissue sections of any other tumor tested, with the exception of ependymoma. Three proteins with molecular weights of 300,000, 185,000, and 90,000 were isolated from SIM-1 membrane extracts by HBA-71 affinity chromatography. Trypsin treatment of intact SIM-1 cells destroys the HBA-71 epitope and cleaves off two proteins with molecular weights of 210,000 and 95,000. HBA-71 antigen expression is not influenced by treatment of ES cell lines with differentiation inducers. Within normal tissues reactivity was observed with the adenohypophysis, ependymal cells, endocrine pancreas, Sertoli, and ovary granulosa cells. The reagent links ES with PNET and provides a highly valuable probe for (a) the immunohistological differential diagnosis of ES/PNET using fresh tissue or paraffin sections from other small round cell tumors, (b) the histogenetic studies of ES/PNET, and (c) the in vivo diagnostic and therapeutic procedures in patients with ES and PNET.

Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases.

The identification of 8-ethyl-2-phenylamino-8H-pyrido[2, 3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2, 3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC(50) = 0.004 microM ([ATP] = 25 microM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb(+) cells in the G(1)-phase of the cell division cycle.

Transsternal operations in thyroid cancer.

Large thyroid carcinomas extending into the anterior mediastinum were removed from six patients by a transsternal surgical approach (partial median sternotomy). Transcervical mediastinal dissection offers obscure exposure and therefore entails the risk of the operation not being radical. The transsternal procedure was used as an alternative to remove affected lymphatic and fatty tissue from an additional nine patients. Sternal metastases were extirpated from 10 patients. Irrespective of the stage of the tumor, the indications for a transsternal approach to onocologically radical extirpation of tumors and mediastinal lymphatic fatty tissue should be more liberal, particularly with differentiated and medullary thyroid carcinomas. The prognosis for differentiated carcinomas is improved by radioiodine treatment, and optimal conditions for this therapy are ensured by the most radical possible removal of the tumor with its affected lymph nodes and sternal metastases. In the case of mixed differentiated/anaplastic and medullary carcinomas, this operative procedure ensures favorable conditions for other adjuvant forms of therapy. Although it was not possible to extend the life expectancy of patients suffering from anaplastic carcinomas, their quality of life was at least improved by the prevention of mechanical dyspnea caused by the mediastinal tumor.

Complications of endoscopic thoracic sympathectomy.

BACKGROUND: Endoscopic resection of the thoracic sympathetic trunk has been performed in various diseases of the upper limb. The success rates in endoscopic techniques and open surgical procedures are reportedly between 95% and 100%. However, the incidence of complications varied significantly depending on the technique used. We report our experience with complications after endoscopic resection of the thoracic sympathetic trunk. METHODS: To evaluate the complications of endoscopic thoracic sympathectomy, we retrospectively investigated 412 patients operated on since 1965. In 412 patients 698 procedures had been performed: a bilateral trunk resection in 81.9%, right thoracic sympathectomy in 12.9%, and left sympathetic trunk resection in 5.2%. RESULTS: Complications demanding intervention were found in 2.7% of the procedures, and in 9.7% complications not indicating active therapy were seen. In all cases requiring intervention a pneumothorax that needed to be drained was found on postoperative x-ray film. An asymptomatic small apical pneumothorax was found in 4.4%, cutaneous emphysema in 2%, pleural effusion in 1.1%, and segmental atelectasis in 0.4% of the procedures. One case of bleeding from an intercostal vessel occurred (0.1%). A permanent Horner's ptosis was seen in 1.7% of the patients. CONCLUSIONS: The endoscopic resection of the thoracic sympathetic trunk is a safe and minimally invasive procedure with a low complication rate. We believe that endoscopic sympathectomy should be preferred to open surgical procedures.

Surgical treatment of distant metastases in differentiated thyroid cancer: indication and results.

A total of 45 patients have received surgical treatment for distant metastases in 41 follicular and four papillary carcinomas. Fifty-four metastatic lesions were removed. In the majority of cases (n = 25, 46%), surgical intervention was indicated on the basis of oncologic data (reduced administration of radioiodine). Sixteen patients (30%) underwent surgery to relieve pain, and 13 other patients (24%) had surgical treatment of pathologic fracture. At the time of surgery, 29 patients (64%) had only one resectable metastasis, while 16 patients (36%) had further nonresectable metastases (six in the bone, 10 in the bones and lungs). In the course of 53 operations, metastases were resected from bone in 46 cases, from the lungs and greater omentum in two cases, and from the skin, suprarenal gland, pleura, and intra-abdominal lymph node in one case each. A total of 25 metastases (17 bone, eight soft tissue) could be removed by resection. In 16 patients, the resulting bone defect was filled with bone cement after resection of the metastases. Osteosynthesis was necessary in another six cases, while seven required the implantation of an endoprosthesis. Thirty-eight patients died between 1 and 136 months after surgical treatment. Twenty-six (58%) died of their primary disease after an average 49.3 months, seven (15%) died with their carcinomas of other causes after an average of 12 months, and five (11%) died intercurrently after an average of 16 months. Seven patients (15%) are still alive after 12 to 264 months (average, 99.3 months); four of them are without recurrence and three have metastases. Five of these patients exhibit normal activity, while the activity of the other two is limited by the progress of the carcinoma or as a result of surgical treatment. The estimated cumulative survival rate (Kaplan-Meier) was 44.8 +/- 11.2% for 5 years and 32.7 +/- 11.0% for 10 years after removal of a solitary metastasis. Analysis of these patients shows that the surgical removal of resectable metastases can be a valuable complement to nuclear medical therapy. The complicated surgical treatment of metastases is justified by the favorable effect it has on prognosis and on the patient's quality of life.