The role of multiparametric magnetic resonance in active surveillance of a low-risk prostate cancer cohort from clinical practice.

INTRODUCTION: Active surveillance (AS) is considered a suitable management practice for those patients with low-risk prostate cancer (PCa). At present, however, the role of multiparametric magnetic resonance imaging (mpMRI) in AS protocols has not yet been clearly established. OUTCOMES: To determine the role of mpMRI and its ability to detect significant prostate cancer (SigPCa) in PCa patients enrolled in AS protocols. MATERIALS AND METHODS: There were 229 patients enrolled in an AS protocol between 2011 and 2020 at Reina Sofía University Hospital. MRI interpretation was based on PIRADS v.1 or v.2/2.1 classification. Demographics, clinical, and analytical data were collected and analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for mpMRI in different scenarios. We defined SigPCa and reclassification/progression as a Gleason score (GS) ≥ 3 + 4, a clinical stage ≥T2b, or an increase in PCa volume. Kaplan-Meier and log-rank tests were used to estimate progression-free survival time. RESULTS: Median age was 69.02 (±7.73) at diagnosis, with a 0.15 (±0.08) PSA density (PSAD). Eighty-six patients were reclassified after confirmatory biopsy, with a suspicious mpMRI an indication for a clear reclassification and risk-predictor factor in disease progression (p < 0.05). During follow-up, 46 patients were changed from AS to active treatment mainly due to disease progression. Ninety patients underwent ≥2mpMRI during follow-up, with a median follow-up of 29 (15-49) months. Thirty-four patients had a baseline suspicious mpMRI (at diagnostic or confirmatory biopsy): 14 patients with a PIRADS 3 and 20 patients with ≥PIRADS 4. From 14 patients with a PIRADS 3 baseline mpMRI, 29% progressed radiologically, with a 50% progression rate versus 10% (1/10 patients) for those with similar or decreased mpMRI risk. Of the 56 patients with a non-suspicious baseline mpMRI (PIRADS < 2), 14 patients (25%) had an increased degree of radiological suspicion, with a detection rate of SigPCa of 29%. The mpMRI NPV during follow-up was 0.91. CONCLUSION: A suspicious mpMRI increases the reclassification and disease progression risk during follow-up and plays an important role in monitoring biopsies. In addition, a high NPV at mpMRI follow-up can help to decrease the need to monitor biopsies during AS.

Initial experience with intraoperative testing and repair of colorectal anastomosis using a TAMIS approach after a positive leak test.

Anastomotic leak is one of the most feared complications of colorectal anastomosis. Different techniques have been described for intraoperative testing of anastomotic integrity. These include air insufflation, methylene blue and endoscopic visualisation. If an anastomotic leak is identified intraoperatively, there are various management options. Redo anastomosis is a possibility, but may be difficult in some cases. Defunctioning is another option, but there is an associated morbidity and signficant detrimental effect on quality of life. Direct transanal repair is only possible when a low anastomosis has been performed. When the anastomotic leak occurs high in the rectum or a partial mesorectal excision is performed a transanal approach is technically very challenging. We present our experience with transanal minimally invasive surgery (TAMIS) approach for anastomotic assessment and repair in four patients. In all cases, a colorectal anastomosis was performed and the air insufflation test was positive. We assessed the anastomosis with TAMIS. In three cases, a defect was found and subsequently sutured. In one case, a scar in the rectal mucosa was found and reinforced with a suture. A protective ileostomy was performed in two cases, while in the other two cases, no stoma was added. All four patients were discharged with no further complications. Both protective ileostomies were taken down after radiological and endoscopic confirmation of anastomotic integrity and all 4 anastomoses remain intact after follow-up. TAMIS intraoperative assessment and repair of anastomotic leak is a safe and feasible technique whcih may avoid the need for a defunctioning stoma.

Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer.

BACKGROUND: In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab-paclitaxel in aTNBC. PATIENTS AND METHODS: Eligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint. RESULTS: Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab-paclitaxel versus 5.7 months with placebo-paclitaxel]. In the PD-L1-positive population, atezolizumab-paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo-paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab-paclitaxel versus 28.3 months with placebo-paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug. CONCLUSION: Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone. CLINICALTRIALS.GOV: NCT03125902.

The heme-sensitive regulator SbnI has a bifunctional role in staphyloferrin B production by Staphylococcus aureus.

Staphylococcus aureus infection relies on iron acquisition from its host. S. aureus takes up iron through heme uptake by the iron-responsive surface determinant (Isd) system and by the production of iron-scavenging siderophores. Staphyloferrin B (SB) is a siderophore produced by the 9-gene sbn gene cluster for SB biosynthesis and efflux. Recently, the ninth gene product, SbnI, was determined to be a free l-serine kinase that produces O-phospho-l-serine (OPS), a substrate for SB biosynthesis. Previous studies have also characterized SbnI as a DNA-binding regulatory protein that senses heme to control sbn gene expression for SB synthesis. Here, we present crystal structures at 1.9-2.1 Å resolution of a SbnI homolog from Staphylococcus pseudintermedius (SpSbnI) in both apo form and in complex with ADP, a product of the kinase reaction; the latter confirmed the active-site location. The structures revealed that SpSbnI forms a dimer through C-terminal domain swapping and a dimer of dimers through intermolecular disulfide formation. Heme binding had only a modest effect on SbnI enzymatic activity, suggesting that its two functions are independent and structurally distinct. We identified a heme-binding site and observed catalytic heme transfer between a heme-degrading protein of the Isd system, IsdI, and SbnI. These findings support the notion that SbnI has a bifunctional role contributing precursor OPS to SB synthesis and directly sensing heme to control expression of the sbn locus. We propose that heme transfer from IsdI to SbnI enables S. aureus to control iron source preference according to the sources available in the environment.

New

Precise antineutrino measurements are very sensitive to proper background characterization. We present an improved measurement of the ^{13}C(α,n)^{16}O reaction cross section which constitutes significant background for large ν[over ¯] detectors. We greatly improve the precision and accuracy by utilizing a setup that is sensitive to the neutron energies while making measurements of the excited state transitions via secondary γ-ray detection. Our results shows a 54% reduction in the background contributions from the ^{16}O(3^{-},6.13 MeV) state used in the KamLAND analysis.

Occurrence of pyrethroid resistance mutation in Cydia pomonella (Lepidoptera: Tortricidae) throughout Argentina.

Pyrethroid insecticides were intensively used against Cydia pomonella in the Río Negro and Neuquén valley, main production area of pome fruits in Argentina. Therefore, the first objective was to evaluate lambda-cyhalothrin resistance levels in C. pomonella larvae from orchards in this area that are currently under pyrethroids treatments. The second objective was to evaluate the frequency of kdr mutation in C. pomonella across Argentina. High levels of resistance to lambda-cyhalothrin (resistance ratios > 30) were determined in all the populations evaluated. The L1014F (kdr) mutation was evaluated in 355 diapausing larvae collected in 12 orchards from San Juan to Santa Cruz provinces (1690 km away from each other). The highest frequency of kdr mutation was determined in larvae from the Río Negro and Neuquén valley (0.61), followed by those from Mendoza (0.36). The kdr allele was absent or present at very low frequencies in orchards subjected to low pyrethroid pressure. The frequency of detection of kdr mutation in C. pomonella from Argentina is related to the use of pyrethroids against this pest in different areas. Target-site insensitivity is, at least, one of the mechanisms involved in resistance to lambda-cyhalothrin in codling moth from the Río Negro and Neuquén valley.

Long cavity ring fiber mode-locked laser with decreased net value of nonlinear polarization rotation.

We investigate a new configuration of a mode-locked fiber laser by using a nonlinear polarization rotation-based design to generate soliton pulses with low repetition rate. Unlike with previously reported configurations, we introduce a Faraday mirror after the first half of the cavity length to counteract the nonlinear polarization rotation effects. The total cavity length is 437 m including a 400-m long twisted SMF-28 fiber. The fiber was twisted to cancel the linear birefringence and to ensure that the polarization ellipticity is not altered as the pulse travels along the fiber. The strict control of polarization yields a stable relation between the polarization state of the pulses propagating in the cavity and the regimes of generation. Depending on the polarization state we observed three different emission regimes, the single soliton regime (SR), conventional noise-like pulses (NLP) and noise-like square-waveform pulse (NLSWP). In the SR, a 467.2 kHz train of solitons was obtained with pulse duration of 2.9 ps at 1558.7 nm.

Staphylococcus aureus heme and siderophore-iron acquisition pathways.

Staphylococcus aureus is a versatile opportunistic human pathogen. Infection by this bacterium requires uptake of iron from the human host, but iron is highly restricted in this environment. Staphylococcus aureus iron sufficiency is achieved primarily through uptake of heme and high-affinity iron chelators, known as siderophores. Two siderophores (staphyloferrins) are produced and secreted by S. aureus into the extracellular environment to capture iron. Staphylococcus aureus expresses specific uptake systems for staphyloferrins and more general uptake systems for siderophores produced by other microorganisms. The S. aureus heme uptake system uses highly-specific cell surface receptors to extract heme from hemoglobin and hemoglobin-haptoglobin complexes for transport into the cytoplasm where it is degraded to liberate iron. Initially thought to be independent systems, recent findings indicate that these iron uptake pathways intersect. IruO is a reductase that releases iron from heme and some ferric-siderophores. Moreover, multifunctional SbnI produces a precursor for staphyloferrin B biosynthesis, and also binds heme to regulate expression of the staphyloferrin B biosynthesis pathway. Intersection of the S. aureus iron uptake pathways is hypothesized to be important for rapid adaptation to available iron sources. Components of the heme and siderophore uptake systems are currently being targeted in the development of therapeutics against S. aureus.

Low frequency of positive antithyroid antibodies is observed in patients with thyroid dysfunction related to immune check point inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICI), such as programmed death-1 inhibitors (anti-PD1), have become a cornerstone for the treatment of different advanced cancers. These antibodies act as modulators of immune checkpoint proteins. However, ICI can lead to the breaking of immune self-tolerance, inducing autoimmune side effects (irAEs), including endocrinopathies. One of the most frequent endocrine irAE of anti-PD1 is thyroid dysfunction, but the exact mechanism of this disease still remains unknown. MATERIALS AND METHODS: We conducted a descriptive retrospective study, analyzing 11 patients who received at least one dose of anti-PD1 (nivolumab or pembrolizumab) and presented thyroid irAEs. Data were collected between September 2015 and May 2018 in our hospital. The aim was to analyze the clinically relevant features of thyroid irAEs and the frequency of antithyroid antibodies (ATA) positivity observed on them. RESULTS AND DISCUSSION: 8 of the 11 patients were treated with nivolumab and the other three patients received pembrolizumab. Six patients presented silent thyroiditis with a thyrotoxicosis phase; three patients developed directly primary/subclinical hypothyroidism and two patients showed primary hyperthyroidism. Thyroid autoantibodies (anti-Thyroglobulin and anti-Thyroid Peroxidase) were assessed in all the 11 patients, and only in two of them (18%) a positive titer was displayed. Anti-TSH receptor antibodies (TRAbs) were examined in five patients, three with painless thyroiditis at the time of thyrotoxicosis and two with primary hyperthyroidism, and they all had undetectable levels. CONCLUSIONS: In our sample of 11 Caucasian patients with thyroid dysfunction related with anti-PD1, we found low frequency of ATA positive titers, comparable to other recent reports in others ethnicities, which could suggest that silent thyroiditis due to pembrolizumab or nivolumab has a different pathogenesis from the classical autoimmune spontaneous thyroiditis. Further investigations are required to completely understand the immune mechanisms involved.

Abrupt-tapered fiber filter arrangement for a switchable multi-wavelength and tunable Tm-doped fiber laser.

A switchable and tunable multi-wavelength Tm-doped fiber laser is successfully demonstrated using a filter constructed with two tapered fiber elements in the cavity. The proposed system design uses a low-cost simple filter that allows stable dual, triple, quadruple, and quintuple-wavelength emission operation in the region around 1.9 µm. In the dual wavelength regime, the laser is capable of independently tuning each wavelength. For switching and tuning, a curvature is applied to the tapered fibers.

Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer.

BACKGROUND: The purpose of this analysis was to assess the long-term impact of adding bevacizumab to adjuvant chemotherapy for early triple-negative breast cancer (TNBC). METHODS: Patients eligible for the open-label randomized phase III BEATRICE trial had centrally confirmed triple-negative operable primary invasive breast cancer (pT1a-pT3). Investigators selected anthracycline- and/or taxane-based chemotherapy for each patient. After definitive surgery, patients were randomized 1:1 to receive ≥4 cycles of chemotherapy alone or with 1 year of bevacizumab (5 mg/kg/week equivalent). Stratification factors were nodal status, selected chemotherapy, hormone receptor status, and type of surgery. The primary end point was invasive disease-free survival (IDFS; previously reported). Secondary outcome measures included overall survival (OS) and safety. RESULTS: After 56 months' median follow-up, 293 of 2591 randomized patients had died. There was no statistically significant difference in OS between treatment arms in either the total population (hazard ratio 0.93, 95% confidence interval [CI] 0.74-1.17; P = 0.52) or pre-specified subgroups. The 5-year OS rate was 88% (95% CI 86-90%) in both treatment arms. Updated IDFS results were consistent with the primary IDFS analysis. Five-year IDFS rates were 77% (95% CI 75-79%) with chemotherapy alone versus 80% (95% CI 77-82%) with bevacizumab. From 18 months after first study dose to study end, new grade ≥3 adverse events occurred in 4.6% and 4.5% of patients in the two arms, respectively. CONCLUSION: Final OS results showed no significant benefit from bevacizumab therapy for early TNBC. Late-onset toxicities were rare in both groups. Five-year OS and IDFS rates suggest that the prognosis for patients with TNBC is better than previously thought. CLINICALTRIALS.GOV: NCT00528567.

Compound heterozygous mutations in the IFT140 gene cause Opitz trigonocephaly C syndrome in a patient with typical features of a ciliopathy.

〈 We report on an infant with Opitz trigonocephaly C syndrome (OTCS), who also had manifestations of ciliopathy, including short ribs (non-asphyxiating), trident acetabular roofs, postaxial polydactyly cone-shaped epiphyses, and dysplasia of the renal, hepatic and pancreatic tissues. To investigate the molecular cause, we used an exome sequencing strategy followed by Sanger sequencing. Two rare variants, both predicted to result in loss of functional protein, were identified in the IFT140 gene; a substitution at the splice donor site of exon 24 (c.723 + 1 G > T) and a 17 bp deletion, impacting the first coding exon (c.-11_6del). The variants were confirmed as being biallelic using Sanger sequencing, showing that the splice variant was inherited from the propositus mother and the deletion from the father. To date, Mainzer-Saldino syndrome, Jeune syndrome, and a form of nonsyndromic retinal dystrophy, have been identified as ciliopathies caused by IFT140 mutations. We provide the first description of an OTCS phenotype that appears to result from IFT140 mutations. The presentation of this patient is consistent with previous reports showing that OTCS already exhibited skeleletal and nonskeletal features of a ciliopathy.

Initial conditions for dissipative solitons in a strict polarization-controlled passively mode-locked Er-Fiber laser.

We report the dynamics of dissipative solitons in a ring cavity passively mode-locked fiber laser with a strict control of the polarization state. We study the relation between the polarization state of the pulses propagating in the cavity and the regimes of generation. We have found that at pulse ellipticities between 5° and 15°, the laser generates one bunch of pulses in the cavity, while at higher ellipticities the laser generates multiple bunches. At constant ellipticity we rotated the polarization azimuth and observed a regime transition from the generation of noise-like pulses (NLP) to that of soliton crystal. The NLP regime was found when the azimuth was rotated towards smaller low-power transmission through the polarizer. The number of solitons in the soliton crystal also depended on the azimuth in a straightforward way: the higher the initial transmission, the bigger the number of solitons.

Validity assessment of the PROMIS fatigue domain among people living with HIV.

PURPOSE: To evaluate psychometric characteristics and cross-sectional and longitudinal validity of the 7-item PROMIS® Fatigue Short Form and additional fatigue items among people living with HIV (PLWH) in a nationally distributed network of clinics collecting patient reported data at the time of routine clinical care. METHODS: Cross-sectional and longitudinal fatigue data were collected from September 2012 through April 2013 across clinics participating in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS). We analyzed data regarding psychometric characteristics including simulated computerized adaptive testing and differential item functioning, and regarding associations with clinical characteristics. RESULTS: We analyzed data from 1597 PLWH. Fatigue was common in this cohort. Scores from the PROMIS® Fatigue Short Form and from the item bank had acceptable psychometric characteristics and strong evidence for validity, but neither performed better than shorter instruments already integrated in CNICS. CONCLUSIONS: The PROMIS® Fatigue Item Bank is a valid approach to measuring fatigue in clinical care settings among PLWH, but in our analyses did not perform better than instruments associated with less respondent burden.

New amino acid changes in drug resistance sites and HBsAg in hepatitis B virus genotype H.

Long-term treatment with retrotranscriptase (RT) inhibitors eventually leads to the development of drug resistance. Drug-related mutations occur naturally and these can be found in hepatitis B virus (HBV) carriers who have never received antiviral therapy. HBsAg are overlapped with RT domain, thus nucleot(s)ide analogues (NAs) resistance mutations and naturally-occurring mutations can cause amino acid changes in the HBsAg. Twenty-two patients with chronic hepatitis B were enrolled; three of them were previously treated with NAs and 19 were NAs-naïve treated. HBV reverse transcriptase region was sequenced; genotyping and analysis of missense mutations were performed in both RT domain and HBsAg. There was predominance of genotype H. Drug mutations were present in 18.2% of patients. Classical lamivudine resistance mutations (rtM204V/rtL180M) were present in one naïve-treatment patient infected with genotype G. New amino acid changes were identified in drug resistance sites in HBV strains from patients infected with genotype H; rtQ215E was present in two naïve-NAs treatment patients and rtI169M was identified in a patient previously treated with lamivudine. Mutations at sites rt169, rt204, and rt215 resulted in the Y161C, I195M, and C206W mutations at HBsAg. Also, new amino acid changes were identified in B-cell and T-cell epitopes and were more frequent in HBsAg compared to RT domain. In conclusion, new amino acid changes at antiviral resistance sites, B-cell and T-cell epitopes in HBV genotype H were identified in Mexican patients.

Effects of chronic cocaine treatment during adolescence in Lewis and Fischer-344 rats: Novel location recognition impairment and changes in synaptic plasticity in adulthood.

The use of Lewis (LEW) together with Fischer-344 (F344) rats has been proposed as an addiction model because of the addiction behavior differences of these two strains. We have previously suggested that these differences could be related to learning and memory processes and that they depend on the genetic background of these two strains of rats. Adolescence is a period of active synaptic remodeling, plasticity and particular vulnerability to the effects of environmental insults such as drugs of abuse. We have evaluated spatial memory using novel location recognition in LEW and F344 adult rats undergoing a chronic treatment with cocaine during adolescence or adulthood. In order to study whether synaptic plasticity mechanisms were involved in the possible changes in learning after chronic cocaine treatment, we carried out electrophysiological experiments in hippocampal slices from treated animals. Our results showed that, in LEW cocaine-treated rats, hippocampal memory was only significantly impaired when the drug was administered during adolescence whereas adult administration did not produce any detrimental effect in spatial memory measured in this protocol. Moreover, F344 rats showed clear difficulties carrying out the protocol even in standard conditions, confirming the spatial memory problems observed in previous reports and demonstrating the genetic differences in spatial learning and memory. Our experiments show that the effects in behavioral experiments are related to synaptic plasticity mechanisms. Long-term depression induced by the glutamate agonist NMDA (LTD-NMDA) is partially abolished in cocaine-treated animals in hippocampal slices from LEW rats. Hippocampal LTD-NMDA is partially inhibited in F344 animals regardless of whether saline or cocaine administration, suggesting the lack of plasticity of this strain that could be related to the inability of these animals to carry out the novel object location protocol.

Towards light-mediated sensing of bacterial comfort.

UNLABELLED: Bacterial comfort is central to biotechnological applications. Here, we report the characterization of different sensoring systems, the first step within a broader synthetic biology-inspired light-mediated strategy to determine Escherichia coli perception of environmental factors critical to bacterial performance. We did so by directly 'asking' bacterial cultures with light-encoded questions corresponding to the excitation wavelength of fluorescent proteins placed under the control of environment-sensitive promoters. We built four genetic constructions with fluorescent proteins responding to glucose, temperature, oxygen and nitrogen; and a fifth construction allowing UV-induced expression of heterologous genes. Our engineered strains proved able to give feedback in response to key environmental factors and to express heterologous proteins upon light induction. This light-based dialoguing strategy reported here is the first effort towards developing a human-bacteria interphase with both fundamental and applied implications. SIGNIFICANCE AND IMPACT OF THE STUDY: The results we present here are at the core of a larger synthetic biology research effort aiming at establishing a dialogue with bacteria. The framework is to convert the human voice into electric pulses, these into light pulses exciting bacterial fluorescent proteins, and convert light-emission back into electric pulses, which will be finally transformed into synthetic voice messages. We report here the first results of the project, in the form of light-based determination of key parameters for bacterial comfort. The ultimate goal of this strategy is to combine different engineered populations to have a combined feedback from the pool.