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Purpose The prostate-specific membrane antigen (PSMA) targeted positron-emitting-tomography (PET) tracer 68 Ga-PSMA-11 shows great promise in the detection of prostate cancer. However, 68 Ga has several shortcomings as a radiolabel including short half-life and non-ideal energies, and this has motivated consideration of 18 F-labelled analogs. 18 F-PSMA-1007 was selected among several 18 F-PSMA-ligand candidate compounds because it demonstrated high labelling yields, outstanding tumor uptake and fast, non-urinary background clearance. Here, we describe the properties of 18 F-PSMA-1007 in human volunteers and patients. Methods Radiation dosimetry of 18 F-PSMA-1007 was determined in three healthy volunteers who underwent whole-body PET-scans and concomitant blood and urine sampling. Following this, ten patients with high-risk prostate cancer underwent 18 F-PSMA-1007 PET/CT (1 h and 3 h p.i.) and normal organ biodistribution and tumor uptakes were examined. Eight patients underwent prostatectomy with extended pelvic lymphadenectomy. Uptake in intra-prostatic lesions and lymph node metastases were correlated with final histopathology, including PSMA immunostaining. Results With an effective dose of approximately 4.4–5.5 mSv per 200–250 MBq examination, 18 F-PSMA-1007 behaves similar to other PSMA-PET agents as well as to other 18 F-labelled PET-tracers. In comparison to other PSMA-targeting PET-tracers, 18 F-PSMA-1007 has reduced urinary clearance enabling excellent assessment of the prostate. Similar to 18 F-DCFPyL and with slightly slower clearance kinetics than PSMA-11, favorable tumor-to-background ratios are observed 2–3 h after injection. In eight patients, diagnostic findings were successfully validated by histopathology. 18 F-PSMA-1007 PET/CT detected 18 of 19 lymph node metastases in the pelvis, including nodes as small as 1 mm in diameter. Conclusion 18 F-PSMA-1007 performs at least comparably to 68 Ga-PSMA-11, but its longer half-life combined with its superior energy characteristics and non-urinary excretion overcomes some practical limitations of 68 Ga-labelled PSMA-targeted tracers.

R2TP is an HSP90 co-chaperone that assembles important macro-molecular machineries. It is composed of an RPAP3-PIH1D1 heterodimer, which binds the two essential AAA+ATPases RUVBL1/RUVBL2. Here, we resolve the structure of the conserved C-terminal domain of RPAP3, and we show that it directly binds RUVBL1/RUVBL2 hexamers. The human genome encodes two other proteins bearing RPAP3-C-terminal-like domains and three containing PIH-like domains. Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP. This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. Remarkably, R2SP is required for liprin-α2 expression and for the assembly of liprin-α2 complexes, indicating that R2SP functions in quaternary protein folding. Effects are stronger at 32 °C, suggesting that R2SP could help compensating the lower temperate of testis. R2TP is an HSP90 co-chaperone composed of an RPAP3-PIH1D1 heterodimer, which binds two essential AAA+ ATPases RUVBL1/RUVBL2. Here authors use a structural approach to study RPAP3 and find an RPAP3-like protein (SPAG1) which also forms a co-chaperone complex with PIH1D2 and RUVBL1/2 enriched in testis.

Background Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is becoming standard of care for men with biochemical recurrence (BCR) of prostate cancer. The implications of a negative PSMA PET/CT scan in this population remain unclear. This study aims to assess the outcome of patients with BCR post radical prostatectomy (RP) who have negative [ 18 F]DCFPyL PET/CT scan at relapse. Methods This is a post-hoc subgroup analysis of a prospective non randomized clinical trial. One hundred and one patients (median age, 75 years) with BCR after RP, who tested negative on [ 18 F]DCFPyL PET/CT and subsequently either underwent salvage radiotherapy (sRT) with or without androgen deprivation therapy (ADT) or were followed without active treatment, were included. Freedom from progression (FFP) after negative PSMA PET/CT was determined based on follow-up imaging selected as per clinical practice. Uni- and multivariate Cox regression analyses were performed to examine the association of patients' characteristics, tumor-specific variables, and treatment with clinical progression at the last follow-up. FFP at 1-, 2-, and 3-year were reported using Kaplan Meier analysis. Results The median PSA level at PET/CT was 0.56 ng/mL (range, 0.4–11.3). Sixty five (64%) patients were followed without receiving further treatment, and 36 (36%) received sRT (18% to the prostate bed only and 18% to the prostate bed and pelvic lymph nodes) within 3 months of the PSMA PET. Seventeen of the sRT patients (17 of 36, 47%) received concomitant androgen deprivation therapy (ADT). Median follow-up was 39 months. Subsequent clinical progression was detected in 21 patients (21%), with 52% in pelvic lymph nodes, 52% in the prostatic fossa, 19% in distant lymph nodes, 14% in lungs, and 10% in bones. The FFP was 95% (95% CI: 91%-99%) at 12 months, 87% (95% CI: 81%-94%) at 24 months, and 79% (95% CI: 71%-88%) at 36 months. Multivariate Cox regression analysis revealed that an initial International Society of Urological Pathology (ISUP) grade 5 was significantly associated with clinical progression at the last follow-up (hazard ratio, 5.1, P value, 0.04). Furthermore, the receipt of sRT correlated significantly with lower clinical progression at the last follow-up (hazard ratio, 0.2, P value, 0.03), whereas other clinical and tumor-specific parameters did not. Following surveillance-only and sRT, 29% (19 of 65) and 6% (2 of 36) of patients, respectively, showed clinical progression. In the sRT group, no significant difference was observed in FFP between patients who underwent sRT to the prostatic fossa versus those who received sRT to the prostatic fossa and pelvic lymph nodes, although the numbers in these groups were small. Conclusions This study suggests that salvage radiotherapy is associated with a decreased or delayed clinical progression in patients with biochemical recurrence following radical prostatectomy who have negative PSMA PET/CT scan results. The analysis also underscores the prognostic significance of the initial ISUP grade, with ISUP grade 5 being associated with worse outcomes. Trial registration Registered September 14, 2016; NCT02899312 .

Chronic hepatitis B virus (HBV) infection is a major health burden potentially evolving toward cirrhosis and hepatocellular carcinoma. HBV physiopathology is strongly related to the host immunity, yet the mechanisms of viral evasion from immune-surveillance are still misunderstood. The immune response elicited at early stages of viral infection is believed to be important for subsequent disease outcome. Dendritic cells (DCs) are crucial immune sentinels which orchestrate antiviral immunity, which offer opportunity to pathogens to subvert them to escape immunity. Despite the pivotal role of DCs in orientating antiviral responses and determining the outcome of infection, their precise involvement in HBV pathogenesis is not fully explored. One hundred thirty chronically HBV infected patients and 85 healthy donors were enrolled in the study for blood collection, together with 29 chronically HBV infected patients and 33 non-viral infected patients that were included for liver biopsy collection. In a pioneer way, we investigated the phenotypic and functional features of both circulating and intrahepatic BDCA1+ cDC2, BDCA2+ pDCs, and BDCA3+ cDC1 simultaneously in patients with chronic HBV infection by designing a unique multi-parametric flow cytometry approach. We showed modulations of the frequencies and basal activation status of blood and liver DCs associated with impaired expressions of specific immune checkpoints and TLR molecules on circulating DC subsets. Furthermore, we highlighted an impaired maturation of circulating and hepatic pDCs and cDCs following stimulation with specific TLR agonists in chronic HBV patients, associated with drastic dysfunctions in the capacity of circulating DC subsets to produce IL-12p70, TNFα, IFNα, IFNλ1, and IFNλ2 while intrahepatic DCs remained fully functional. Most of these modulations correlated with HBsAg and HBV DNA levels. We highlight potent alterations in the distribution, phenotype and function of all DC subsets in blood together with modulations of intrahepatic DCs, revealing that HBV may hijack the immune system by subverting DCs. Our findings provide innovative insights into the immuno-pathogenesis of HBV and the mechanisms of virus escape from immune control. Such understanding is promising for developing new therapeutic strategies restoring an efficient immune control of the virus.

Plant sterols and stanols inhibit intestinal cholesterol absorption and consequently lower serum LDL-cholesterol (LDL-C) concentrations. The underlying mechanisms are not yet known. In vitro and animal studies have suggested that changes in intestinal sterol metabolism are attributed to the LDL-C-lowering effects of plant stanol esters. However, similar studies in human subjects are lacking. Therefore, we examined the effects of an acute intake of plant stanol esters on gene expression profiles of the upper small intestine in healthy volunteers. In a double-blind cross-over design, fourteen healthy subjects (eight female and six male; age 21–55 years), with a BMI ranging from 21 to 29 kg/m2, received in random order a shake with or without plant stanol esters (4 g). At 5 h after consumption of the shake, biopsies were taken from the duodenum (around the papilla of Vater) and from the jejunum (20 cm distal from the papilla of Vater). Microarray analysis showed that the expression profiles of genes involved in sterol metabolism were not altered. Surprisingly, the pathways involved in T-cell functions were down-regulated in the jejunum. Furthermore, immunohistochemical analysis showed that the number of CD3 (cluster of differentiation number 3), CD4 (cluster of differentiation number 4) and Foxp3+ (forkhead box P3-positive) cells was reduced in the plant stanol ester condition compared with the control condition, which is in line with the microarray data. The physiological and functional consequences of the plant stanol ester-induced reduction of intestinal T-cell-based immune activity in healthy subjects deserve further investigation.

Benign prostatic hyperplasia (BPH) treatment includes the apoptosis machinery modulation through the direct inhibition of caspase cascade. We previously demonstrated that Serenoa repens (Ser) with lycopene (Ly) and selenium (Se) reawakened apoptosis by reducing survivin and neuronal apoptosis inhibitory protein (NAIP) levels in rats. The aim of this study was to evaluate the effectiveness of Ser-Se-Ly association on survivin and NAIP expression in BPH patients. Ninety patients with lower urinary tract symptoms (LUTS) due to clinical BPH were included in this randomized, double-blind, placebo-controlled trial. Participants were randomly assigned to receive placebo (Group BPH + placebo, n = 45) or Ser-Se-Ly association (Group BPH + Ser-Se-Ly; n = 45) for 3 months. At time 0, all patients underwent prostatic biopsies. After 3 months of treatment, they underwent prostatic re-biopsy and specimens were collected for molecular, morphological, and immunohistochemical analysis. After 3 months, survivin and NAIP were significantly decreased, while caspase-3 was significantly increased in BPH patients treated with Ser-Se-Ly when compared with the other group. In BPH patients treated with Ser-Se-Ly for 3 months, the glandular epithelium was formed by a single layer of cuboidal cells. PSA showed high immunoexpression in all BPH patients and a focal positivity in Ser-Se-Ly treated patients after 3 months. Evident prostate specific membrane antigen (PSMA) immunoexpression was shown in all BPH patients, while no positivity was present after Ser-Se-Ly administration. Ser-Se-Ly proved to be effective in promoting apoptosis in BPH patients.

Chronic hepatitis B virus (HBV) infection results from inadequate HBV-specific immunity. BDCA3+ dendritic cells (DCs) are professional antigen presenting cells considered to be important for antiviral responses because of specific characteristics, including high interferon-λ production. BDCA3+ DCs may thus also have a role in the immune response against HBV, and immunotherapeutic strategies aiming to activate DCs, including BDCA3+ DCs, in patient livers may represent an interesting treatment option for chronic HBV. However, neither the effect of chronic hepatitis B (CHB) infection on the frequency and function of BDCA3+ DCs in liver and blood, nor the effect of the viral surface protein (HBsAg) that is abundantly present in blood of infected individuals are known. Here, we provide an overview of BDCA3+ DC frequency and functional capacity in CHB patients. We find that intrahepatic BDCA3+ DC numbers are increased in CHB patients. BDCA3+ DCs from patient blood are not more mature at steady state, but display an impaired capacity to mature and to produce interferon-λ upon polyI:C stimulation. Furthermore, in vitro experiments exposing blood and intrahepatic BDCA3+ DCs to the viral envelope protein HBsAg demonstrate that HBsAg does not directly induce phenotypical maturation of BDCA3+ DCs, but may reduce IFN-λ production via an indirect unknown mechanism. These results suggest that BDCA3+ DCs are available in the blood and on site in HBV infected livers, but measures may need to be taken to revive their function for DC-targeted therapy.

Background The role of antiviral therapy for patients in the immune-active phase of hepatitis B virus (HBV) infection who underwent partial hepatectomy for hepatocellular carcinoma (HCC) is unknown. Methods From January 2004 to June 2007, a nonrandomized comparative study for postoperative antiviral treatment was conducted on patients who underwent curative hepatectomy for advanced HCC. Patients in the treatment group ( n  = 43) received lamivudine with or without adefovir dipivoxil, while the control group ( n  = 36) received no antiviral treatment. Results The treatment group had a significantly higher HBeAg seroconversion rate (57.2% vs. 5.6%) and a higher HBV DNA suppression rate (87.2% vs. 2.8%) after 12 months of antiviral treatment. The treatment group also had a significantly greater increase in residual liver volume per unit surface area following hepatectomy (78.0 ± 40.1 cm 3 /m 2 vs. 35.8 ± 56.0 cm 3 /m 2 ) at 6-month postoperation. After a median follow-up of 12 months, there was no significant difference in recurrence rate after surgery between the treatment group and the control group (76.7% and 91.7%). There was a significant difference in the overall survival rate but not in the disease-free survival rate. The 1- and 2-year overall survival rates were 41.9% and 7.0%, respectively, for the treatment group, and 33.3% and 0%, respectively, for the control group. The 1- and 2-year disease-free survival rates were 23.3% and 2.3%, respectively, for the treatment group, and 8.3% and 0%, respectively, for the control group. Conclusion Although nucleoside analogs did not reduce short-term recurrence rate, they promoted postoperative viral clearance and increased residual liver volume, which significantly enhanced tolerance to subsequent therapy for disease recurrence.

Flow cytometric analysis of cell surface antigens is a powerful tool for the isolation and characterization of stem cells residing in adult tissues. In contrast to the collection of hematopoietic stem cells, the process of enzymatic digestion is usually necessary to prepare mesenchymal stem cells (MSCs) suspensions, which can influence the expression of cell surface markers. In this study, we examined the effects of various cell-detaching reagents and digestion times on the expression of stem cell-related surface antigens and MSC functions. Human MSCs were detached from dishes using four different reagents: trypsin, TrypLE, collagenase, and a non enzymatic cell dissociation reagent (C5789; Sigma-Aldrich). Following dissociation reagent incubations ranging from 5 to 120 min, cell surface markers were analyzed by flow cytometry. Trypsin and TrypLE quickly dissociated the cells within 5 min, while collagenase and C5789 required 60 min to obtain maximum cell yields. C5789 significantly decreased cell viability at 120 min. Trypsin treatment significantly reduced CD44+, CD55+, CD73+, CD105+, CD140a+, CD140b+, and CD201+ cell numbers within 30 min. Collagenase treatment reduced CD140a expression by 30 min. In contrast, TrypLE treatment did not affect the expression of any cell surface antigens tested by 30 min. Despite the significant loss of surface antigen expression after 60 min of treatment with trypsin, adverse effects of enzymatic digestion on multipotency of MSCs were limited. Overall, our data indicated that TrypLE is advantageous over other cell dissociation reagents tested for the rapid preparation of viable MSC suspensions.

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer 1 , 2 , 3 – 4 . A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge 5 , 6 . A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the ‘click’ SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted β- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets. Radiopharmaceuticals engineered with click chemistry to selectively bind to tumour-specific proteins can be used to successfully target tumour cells, boosting the pharmacokinetics of radionuclide therapy and improving tumour regression.