Cervicovaginal microbiota long-term dynamics and prediction of different outcomes in persistent human papillomavirus infection.

Persistent human papillomavirus (HPV) infection can lead to cervical intraepithelial neoplasia (CIN) and cervical cancer, posing serious threats to the health of women. Although the cervicovaginal microbiota is strongly associated with CIN, the dynamics of the microbiota during CIN development are unknown. In this retrospective cohort study, we analyzed 3-year longitudinal data from 72 patients diagnosed with a persistent HPV infection almost all caused by high-risk HPV types. Patients were categorized into groups with HPV persistent infection (n = 37), progression to CIN (n = 16), and CIN regression (n = 19) based on infection outcome during the follow-up period. Furthermore, 16S rRNA gene sequencing was performed on consecutively collected cervical samples to explore the composition and dynamics of the cervicovaginal microbiota during the development and regression of CIN. Our results showed that the composition of the cervicovaginal microbiota varied among women with different HPV infection outcomes and remained relatively stable during the follow-up period. Notably, the serial follow-up data showed that these microbial alterations were present for at least 1-2 years and occurred before pathologic changes. In addition, microbial markers that were highly discriminatory for CIN progression or regression were identified. This study provides evidence for a temporal relationship between changes in the cervicovaginal microbiota and the development of CIN, and our findings provide support for future microbial intervention strategies for CIN.

Mechanistic Insights into Sc(III)-Catalyzed Asymmetric Homologation of Ketones with Diazo Compounds: How Trans Influence Assists in Controlling Stereochemistry.

Asymmetric one-carbon homologation or ring expansion of ketones with formal insertion of carbene intermediate, is a challenging but useful strategy to construct a complex skeleton. Sc(III) and chiral ligands have been employed in this regard. However, due to flexible conformations and a variety of stereo models, the origin of stereochemistry remains ambiguous. Density functional theory (DFT) calculations were carried out to explore the interactions that control the stereoselectivity of a Sc(III)-catalyzed asymmetric homologation. The trans influence of counterions was found to affect the coordination mode of ketone to Sc(III), and consequently affect the stereoselectivity.

Ivabradine monotherapy in pediatric patients with focal atrial tachycardia: a single-center study.

This study investigated the efficacy of ivabradine monotherapy in pediatric patients with focal atrial tachycardia (FAT). We prospectively enrolled 12 pediatric patients (7.5 ± 4.5 years; six girls) with FAT who were resistant to conventional antiarrhythmics and received ivabradine as monotherapy. Patients were classified as having tachycardia-induced cardiomyopathy (TIC) if they had a left ventricular ejection fraction (LVEF) of < 50% and a left ventricular end-diastolic dimension (LVDD) z-score of > 2 due to tachycardia. Oral ivabradine was initiated at 0.1 mg/kg every 12 h, increased to 0.2 mg/kg every 12 h if no restoration of stable sinus rhythm was observed after two doses, and discontinued after 48 h if neither rhythm nor heart rate control was observed. Of these patients, six (50%) had incessant atrial tachycardia, and 6 had frequent short episodes of FAT. Six patients were diagnosed with TIC, and their mean LVEF and mean LVDD z-score were 36.2 ± 8.7% (range, 27-48%) and 4.2 ± 1.7 (range, 2.2-7.3), respectively. Finally, six patients achieved either rhythm (n = 3) or heart rate control (n = 3) within 48 h of ivabradine monotherapy. One patient achieved rhythm/heart rate control with ivabradine at a dose of 0.1 mg/kg every 12 h, while the others achieved rhythm/heart rate control at a dose of 0.2 mg/kg every 12 h. Five patients received ivabradine monotherapy for chronic therapy, one (20%) of whom had FAT breakthrough 1 month after discharge, and metoprolol was added. Neither FAT recurrence nor adverse effect (with or without beta-blocker) was observed during a median follow-up of 5 months. CONCLUSION: Ivabradine is well-tolerated and may provide early heart rate control in pediatric FAT and can be considered early, especially in the presence of left ventricular dysfunction. Further investigations are deserved to confirm the optimal dose and long-term efficacy in this population. WHAT IS KNOWN: • Focal atrial tachycardia (FAT) is the most common arrhythmia associated with tachycardia-induced cardiomyopathy (TIC) in children, and the efficacy of conventional antiarrhythmic medications in the treatment of FAT is poor. • Ivabradine is currently the only selective hyperpolarization-activated cyclic nucleotide-gated (HCN) inhibitor, which can effectively low HR without negative effect on blood pressure or inotropy. WHAT IS NEW: • Ivabradine (0.1-0.2 mg/kg every 12 h) can effectively suppress focal atrial tachycardia in 50% of pediatric patients. • Ivabradine provides early control of heart rate and hemodynamic stabilization in children with severe left ventricular dysfunction due to atrial tachycardia within 48 h.

Stenting of branch pulmonary artery stenosis in children: initial experience and mid-term follow-up of the pul-stent.

Not all stents are suitable for children. For instance, premounted stents can be used in infants and small children but cannot dilate with age to accommodate adult-sized pulmonary arteries. Conversely, the Pul-Stent adapts to somatic growth. Thus, our hospital implemented the Pul-Stent in pediatric patients with branch pulmonary artery stenosis. This study summarizes our initial experience with Pul-Stents in this patient population, including the efficacy and safety. We implanted 37 Pul-Stents in 35 patients between August 2014 and June 2015. The patients' mean age and weight at stent implantation were 6.7 ± 3.0 years and 20.9 ± 8.7 kg, respectively. Bench testing revealed that axial shortening of the Pul-Stent was minimal with further dilation, and the radial strength did not change. The stents were successfully deployed in all cases, except two with minor malpositioning. Primarily, 8-12 mm mounting balloons were used for the initial implantation, and a long sheath (8-10 F) was used for delivery. After stent implantation, the minimal lumen diameter in the stenosed segment increased by 50% in 97% (34/35) of patients. Furthermore, the pressure gradient across the stenosed segment decreased by 50% in 77% (23/30) of biventricular patients. One stent fracture and one stent restenosis were noted during the follow-up visits (mean follow-up time: 4.6 ± 1.7 years). Eighteen patients (51%) underwent repeat catheterization; ten had successful redilation. No aneurysms or stent fractures were observed. Our initial results indicate that the Pul-Stent is safe and effective in pediatric patients and can be further dilated over time to accommodate somatic growth. Moreover, the Pul-Stent has good compliance and adequate radial strength to treat pulmonary artery stenosis effectively.

Intestinal obstruction caused by mesodiverticular band in children: a cohort study.

OBJECTIVE: To explore clinical characteristics, pathogenesis, diagnosis and treatment of intestinal obstruction due to mesodiverticular band (MDB) in children in a single center in China. METHODS: The clinical data of 20 children with acute intestinal obstruction due to MDB between 1998 and 2020 were retrospectively analyzed. RESULTS: The male-to-female ratio was 14:6 in 20 cases. Except one case of 7-month pregnant stillbirth, the cases were aged from 7 days to 14 years, at the median age of 4.31 years. The common symptoms were vomiting, abdominal pain and/or abdominal distension. About 40% (8/20) of patients had both MDB and Meckel's Diverticulum (MD), while 60% (12/20) of patients had MDB only. Only one case died because of total colonic aganglionosis, while other children recovered after surgery treatment. MDB led to the strangulation of necrotic bowel in six cases, intestinal perforation in one case, and intestinal rupture in one case. Pathologic examination showed thick-walled arteries and or thick venous vascular structures in the cord. All cases had no complications during 1-year follow-up. CONCLUSION: MDB results from the remnant of vitelline vessel, and often causes acute intestinal obstruction without special clinical symptoms. Unexplained abdominal pain and distension without surgery history should be paid attention, especially for strangulated intestinal obstruction. Timely surgical exploration is beneficial to avoid intestinal necrosis or even sudden death, and the pathological examination is important for the diagnosis.

Selective Formal Carbene Insertion into Carbon-Boron Bonds of Diboronates by N-Trisylhydrazones.

Bisborylalkanes play important roles in organic synthesis as versatile bifunctional reagents. The two boron moieties in these compounds can be selectively converted into other functional groups through cross-coupling, oxidation or radical reactions. Thus, the development of efficient methods for synthesizing bisborylalkanes is highly demanded. Herein we report a new strategy to access bisborylalkanes through the reaction of N-trisylhydrazones with diboronate, in which the bis(boryl) methane is transformed into 1,2-bis(boronates) via formal carbene insertion. Since the N-trisylhydrazones can be readily derived from the corresponding aldehydes, this strategy represents a practical synthesis of 1,2-diboronates with broad substrate scope. Mechanistic studies reveal an unusual neighboring group effect of 1,1-bis(boronates), which accounts for the observed regioselectivity when unsymmetric 1,1-diboronates are applied.

A Carbene Relay Strategy for Cascade Insertion Reactions.

Insertion reactions that involve stabilized electrophilic metallocarbenes are of great importance for installing α-heteroatoms to carbonyl compounds. Nevertheless, the limited availability of carbene precursors restricts the introduction of only a single heteroatom. In this report, we describe a new approach based on an I(III) /S(VI) reagent that promotes the cascade insertion of heteroatoms. This is achieved by sequentially generating two α-heteroatom-substituted metal carbenes in one reaction. We found that this mixed I(III) /S(VI) ylide reacts efficiently with a transition metal catalyst and an X-H bond (where X=O, N). This transformation leads to the sequential formation of a sulfoxonium- and an X-substituted Rh-carbenes, enabling further reactions with another Y-H bond. Remarkably, a wide range of symmetrical and unsymmetrical α,α-O,O-, α,α-O,N-, and α,α-N,N-subsituted ketones can be prepared under mild ambient conditions. In addition, we successfully demonstrated other cascades, such as CN/CN double amidation, C-H/C-S double insertion, and C-S/Y-H double insertion (where Y=S, N, O, C). Notably, the latter two cascades enabled the simultaneous installation of three functional groups to the α-carbon of carbonyl compounds in a single step. These reactions demonstrate the versatility of our approach, allowing for the synthesis of ketones and esters with multiple α-heteroatoms using a common precursor.

Asymmetric N-Alkylation of 1H-Indoles via Carbene Insertion Reaction.

An intermolecular enantioselective N-alkylation reaction of 1H-indoles has been developed by cooperative rhodium and chiral phosphoric acid catalyzed N-H bond insertion reaction. N-Alkyl indoles with newly formed stereocenter adjacent to the indole nitrogen atom are produced in good yields (up to 95 %) with excellent enantioselectivities (up to >99 % ee). Importantly, both α-aryl and α-alkyl diazoacetates are tolerated, which is extremely rare in asymmetric X-H (X=N, O, S et al.) and C-H insertion reactions. With this method, only 0.1 mol % of rhodium catalyst and 2.5 mol % of chiral phosphoric acid are required to complete the conversion as well as achieve the high enantioselectivity. Computational studies reveal the cooperative relay of rhodium and chiral phosphoric acid, and the origin of the chemo and stereoselectivity.

16S ribosomal assay for early diagnosis of gonococcal meningitis with negative CSF culture: A case report.

Gonococcal meningitis is an exceedingly rare infectious disease, and if not diagnosed and treated in time, it can be severe. We present a case of gonococcal meningitis occurring in a 31-year old healthy woman. She was admitted with fever and persistent headache without urogenital symptoms. Blood cultures were positive and identified as N.gonorrhoeae, but CSF and cervical secretions cultures were both negative. Further testing confirmed the presence of N.gonorrhoeae by 16S ribosomal gene amplification and sequencing in all samples. These results suggest that the case may be a disseminated infection caused by untreated gonorrhea. Our case also shows that nucleic acid detection plays an important role in the rapid and precise diagnosis of gonococcal meningitis and in finding the origin of the pathogen.

Asymmetric Synthesis of Spiro[Azetidine-3,3'-Indoline]-2,2'-Diones via Copper(I)-Catalyzed Kinugasa/C-C Coupling Cascade Reaction.

Spiro[azetidine-indolines] are important scaffolds in diverse bioactive compounds. Current efforts to synthesize spiro[azetidine-indolines] are limited to chiral spiro[azetidine-2,3'-indolines]. Asymmetric synthesis of structurally similar chiral spiro[azetidine-3,3'-indolines] remains unexplored. In this work, the first copper(I)-catalyzed asymmetric Kinugasa/aryl C-C coupling cascade reaction is described. This provides a straightforward access to densely functionalized chiral spiro[azetidine-3,3'-indoline]-2,2'-diones in good yields and with high enantioselectivity.

An improved procedure for isolating adult mouse cardiomyocytes for epicardial activation mapping.

Cardiovascular disease is a leading cause of death and disability worldwide. Although genetically modified mouse models offer great potential for robust research in vivo, in vitro studies using isolated cardiomyocytes also provide an important approach for investigating the mechanisms underlying cardiovascular disease pathogenesis and drug actions. Currently, isolation of mouse adult cardiomyocytes often relies on aortic retrograde intubation under a stereoscopic microscope, which poses considerable technical barriers and requires extensive training. Although a simplified, Langendorff-free method has been used to isolate viable cardiomyocytes from the adult mouse heart, the system requires enzymatic digestions and continuous manual technical operation. This study established an optimized approach that allows isolation of adult mouse cardiomyocytes and epicardial activation mapping of mouse hearts using a Langendorff device. We used retrograde puncture through the abdominal aorta in vivo and enzymatic digestion on the Langendorff perfusion device to isolate adult mouse cardiomyocytes without using a microscope. The yields of isolated cardiomyocytes were amenable to patch clamp techniques. Furthermore, this approach allowed epicardial activation mapping. We used a novel, simplified method to isolate viable cardiomyocytes from adult mouse hearts and to map epicardial activation. This novel approach could be beneficial in more extensive research in the cardiac field.

Randomized trial of different initial intravenous immunoglobulin regimens in Kawasaki disease.

BACKGROUND: We aimed to assess the efficacy of different initial intravenous immunoglobulin (IVIG) regimens in Kawasaki disease (KD) patients to find more cost-effective therapy options. METHODS: A multicenter, open-label, blind-endpoint randomized controlled trial was conducted from January 2014 to December 2015. Patients with KD, within 10 days of illness, were randomly assigned to receive different IVIG regimens (Group A, 2 g/kg once; Group B, 1 g/kg for 2 consecutive days; Group C, 1 g/kg once) and aspirin 30mg/kg/d. Primary outcomes included hours to defervescence and development of coronary artery lesions during the study period. Major secondary outcomes included total fever days, total dose of IVIG, changes of laboratory data, length of stay, and hospitalization expenses. (ClinicalTrials.gov: NCT02439996). RESULTS: A total of 404 patients underwent randomization. No difference was found in the outcomes of defervescence among three groups at 6, 12, 24, and 36 hours after completion of initial IVIG infusion. There were no differences in the incidence of coronary artery lesions during the study period (at week 2, month 1, month 3, and month 6 of illness), changes of laboratory data, total fever days, and length of stay. Group C patients had the lowest total dose of IVIG (mean: 1.2 vs 2.2 vs 2.1 g/kg; P < 0.001) and hospitalization expenses (mean: 8443.8 vs 10798.4 vs 11011.4 Chinese Yuan; P < 0.001) than other two groups. CONCLUSIONS: A single dose of 1g/kg IVIG is a low-cost treatment with the same efficacy as 2 g/kg IVIG and can be an option for the initial therapy of KD patients.

Sustained and Controlled Release of Volatile Precursors for Chemical Vapor Deposition of Graphene at Atmospheric Pressure.

Precursors and catalysts play vital roles in chemical reactions. Considerable efforts have been devoted to the investigation of catalysts for graphene growth by chemical vapor deposition in recent years. However, there has been little research on precursors because of a lack of innovation in term of creating a controllable feeding method. Herein, we present a novel sustained and controlled release approach, and develop a convenient, safe, and potentially scalable feeding system with the assistance of matrix materials and a simple portable feeder. As a result, a highly volatile liquid precursor can be fed accurately to grow large-area, uniform graphene films with optimal properties. This feeding approach will further benefit the synthesis of other two-dimensional materials from various precursors.

Epidemiologic Features of Kawasaki Disease in Shanghai From 2013 Through 2017.

BACKGROUND: We sought to investigate epidemiologic features of Kawasaki disease (KD) in Shanghai from 2013 through 2017 and identify risk factors for coronary artery lesions (CAL). METHODS: As in our previous three surveys, a set of questionnaires and diagnostic guidelines for KD were sent to 50 hospitals providing pediatric medical care in Shanghai. Medical records of KD patients diagnosed from January 2013 through December 2017 were retrospectively analyzed. Multivariate logistic regression analysis was performed to identify risk factors for CAL. RESULTS: A total of 4,452 cases were enrolled. Male-to-female ratio was 1.7:1. The incidence of KD was 68.8 to 107.3 per 100,000 children aged <5 years from 2013 to 2017. Age at onset ranged from 15 days to 14.0 years (median: 1.8 years). KD occurred more frequently in spring and summer. Of 4,325 patients (97.0%) receiving intravenous immunoglobulin (IVIG), 362 (8.4%) were resistant to initial IVIG. CAL occurred in 406 (9.1%) patients, including 118 (2.7%) with medium aneurysms and 31 (0.7%) with giant aneurysms. Recurrent cases were 60 (1.3%). No death was found in this survey. Higher platelet levels, lower albumin levels, male sex, incomplete KD, IVIG resistance, and receiving initial IVIG ≤4 days or >10 days, were independently associated with CAL. CONCLUSIONS: The incidence of KD in Shanghai had substantially increased while the proportion of CAL had substantially decreased as compared with our previous surveys. Higher platelet levels, lower albumin levels, male sex, incomplete KD, IVIG resistance, and receiving initial IVIG ≤4 days or >10 days, were risk factors for CAL.

Protection against fatal pneumonia through mucosal and subcutaneous immunization with the pneumococcal SP0148 protein.

Streptococcus pneumoniae infection is associated with very high morbidity and mortality throughout the world. Vaccines are an effective measure for the reduction of S. pneumoniae infection. In particular, protein vaccines are attracting increasing attention because of their good immunogenicity and wide coverage of serotypes. Therefore, identifying effective protein vaccine targets is important for protein vaccine development. SP0148 is a promising protein vaccine target for S. pneumoniae and is capable of reducing S. pneumoniae colonization in the nasopharynx of mice through the IL-17A pathway. However, the protective effects of SP0148 in fatal pneumococcal infection have not been evaluated. This study used subcutaneous and nasal immunization routes to systematically evaluate the protective effects of the SP0148 protein in fatal pneumococcal infection. Subcutaneous and nasal mucosal immunization with recombinant SP0148 protein produced effective immune protection against infection with a lethal dose of S. pneumoniae and significantly prolonged survival time and increased the survival rate of mice. Furthermore, nasal immunization with SP0148 induced mouse splenocytes to secrete high levels of the cytokines IFN-γ and IL-17A. Both recombinant SP0148 protein and its antiserum inhibited the adhesion of S.pneumoniae D39 to A549 human lung epithelial cells in a dose-dependent manner. In summary, SP0148 induced mice to produce protective immune responses to fatal S. pneumoniae infection, and our results could contribute to the accumulating data on the use of SP0148 protein vaccines.

Synthesis of poly(1,5-diaminonaphthalene) microparticles with abundant amino and imino groups as strong adsorbers for heavy metal ions.

Poly(1,5-diaminonaphthalene) microparticles with abundant reactive amino and imino groups on their surface were synthesized by one-step oxidative polymerization of 1,5-diaminonaphthalene using ammonium persulfate as the oxidant. The molecular, supramolecular, and morphological structures of the microparticles were systematically characterized by IR and UV-vis spectroscopies, elementary analysis, wide-angle X-ray diffractometry, and transmission electron microscopy. The microparticles demonstrate electrical semiconductivity and high resistance to strong acid and alkali, and strong adsorption capability for lead(II), mercury(II), and silver(I) ions. The experimental conditions for adsorption of Pb(II) were optimized by varying the persulfate/monomer ratio, adsorption time, sorbent concentration, and pH value of the Pb(II) solution. The maximum adsorption capacity is 241 mg·g-1 for particles after a 24 h-exposure to a solution at an initial Pb(II) concentration of 29 mM. The adsorption data fit a Langmuir isotherm and follow a pseudo-second-order reaction kinetics. This indicates a chemical adsorption that is typical for a chelation interaction between Pb(II) and amino/imino groups on the sorbent. Graphical abstract Poly(1,5-diaminonaphthalene) microparticles with abundant functional amino and imino groups have been synthesized by one-step direct polymerization of non-volatile 1,5-diaminonaphthalene in aqueous medium for sustainable preparation of high-performance adsorbents to strongly adsorb lead(II), mercury(II), and silver(I) ions.

Strong Adhesion of Graphene Oxide Coating on Polymer Separation Membranes.

Graphene oxide (GO) has been demonstrated as the most promising candidate for surface modification of polymer separation membranes for durable filtration applications. However, the adhesion between GO coating and polymer substrate, as the most essential issue for reliable applications, has been little explored. Herein, we developed a facile high-pressure assisted deposition method to physically anchor GO sheets on microfiltration (MF) and reverse osmosis (RO) membranes, and established a tape test procedure for assessing the adhesion of GO coating to polymer substrates based on the ASTM D3359. Through regulating the GO sources and coating process, we demonstrated that the adhesion depends sensitively on the GO flake size and deposition pressure, whereas the adhesion level dramatically improved from 0B to 5B, with decrease in the lateral size of GO and increase in the coating deposition pressure. The strong GO coatings showed evidently higher water flux than that of weak counterparts. The underlying mechanism was further analyzed and verified. Nanosize of GO and high deposition pressure favor the formation of the conformal morphologies of GO coatings on both MF and RO membranes, which allow strong interfacial van der Waals interaction because of the large contact areas and result in the strong GO coatings on membranes. These results potentially open up a versatile pathway to develop the strong graphene-based coatings on separation membranes.

Correction: The physics and chemistry of graphene-on-surfaces.

Correction for 'The physics and chemistry of graphene-on-surfaces' by Guoke Zhao, Xinming Li, Meirong Huang et al., Chem. Soc. Rev., 2017, 46, 4417-4449.

The physics and chemistry of graphene-on-surfaces.

Graphene has demonstrated great potential in next-generation electronics due to its unique two-dimensional structure and properties including a zero-gap band structure, high electron mobility, and high electrical and thermal conductivity. The integration of atom-thick graphene into a device always involves its interaction with a supporting substrate by van der Waals forces and other intermolecular forces or even covalent bonding, and this is critical to its real applications. Graphene films on different surfaces are expected to exhibit significant differences in their properties, which lead to changes in their morphology, electronic structure, surface chemistry/physics, and surface/interface states. Therefore, a thorough understanding of the surface/interface properties is of great importance. In this review, we describe the major "graphene-on-surface" structures and examine the roles of their properties and related phenomena in governing the overall performance for specific applications including optoelectronics, surface catalysis, anti-friction and superlubricity, and coatings and composites. Finally, perspectives on the opportunities and challenges of graphene-on-surface systems are discussed.

Identification and clinical course of 166 pediatric cardiac tumors.

The aim of this study was to investigate the pathological classifications, clinical features, and natural history of pediatric cardiac tumors to provide a basis for the selection of an appropriate therapeutic method. The medical records of in- or outpatients with cardiac tumors at four hospitals were classified to analyze various types of tumor growth locations, clinical manifestations, surgical indications, and long-term follow-up results. There were 166 patients, including 158 with primary cardiac tumors, six with metastatic cardiac tumors, and two with unclassified cardiac tumors. Among the 158 cases of primary cardiac tumor, 150 were benign and eight were malignant. The rhabdomyoma, fibroma, and myxoma are the most common types of benign cardiac tumors. The major clinical manifestations of cardiac tumors include outflow tract obstruction, arrhythmia, dyspnea, pericardial effusion, heart failure, and seizures. Among the 59 patients who underwent surgery, 49 had primary benign cardiac tumors, eight had primary malignant tumors, and two had malignant metastatic tumors. Post-surgery, nine of the patients had residual tumor tissues that did not significantly affect their hemodynamics. Following surgery, there were two cases of recurrence and nine deaths, including four of benign and five of malignant tumors with mortality rates of 8.2 and 50.0 %, respectively. Of the remaining 107 cases of patients who did not undergo surgery, five (4.7 %) died. CONCLUSION: The primary benign cardiac tumors are the predominant pediatric cardiac tumors, of which rhabdomyoma, fibroma, and myxoma are the most common types. If severe symptoms are nonexistent and the hemodynamics is unaffected, most of the patients can survive in the long term despite the tumors. What is known: • Pediatric cardiac tumors are rare and are predominantly primary and benign. • The symptoms of heart failure, arrhythmia, and outflow obstruction are the most severe complications of cardiac tumors. What is new: • The rhabdomyoma, fibroma, and myxoma are the most common types of primary benign cardiac tumors. • If severe symptoms are not present and the hemodynamics are unaffected, most of the patients can survive in the long term despite the tumors.