Targeted Therapy for Prostate Cancer by Prostate-Specific Membrane Antigen-Targeted Small-Molecule Drug Conjugates.

In the aging global population, prostate cancer is a worldwide health problem because the incidence rate of this disease increases at advanced ages. Although early-stage prostate cancer can be treated by total prostatectomy, the surgery causes side effects, such as incontinence and dysuria, that lower QOL. Once the disease progresses to metastatic castration-resistant prostate cancer (mCRPC), there are no effective chemotherapeutic agents without systematic side effects. Therefore, targeted therapies for mCPRC are urgently needed. Traditional antibody-drug conjugate treatments for prostate cancer have been tested in clinical trials and several side effects have been observed. Meanwhile, small-molecule drug conjugates (SMDCs) have certain advantages over antibody drug conjugates in terms of non-immunogenicity, reproducibility, and permeability. In this review, prostate-specific membrane antigen-targeted SMDCs for treating prostate cancer are summarized.

Decreased Analgesic Effect of Tramadol in Japanese Patients with CYP2D6 Intermediate Metabolizers after Orthopedic Surgery.

Tramadol is metabolized by CYP2D6 to an active metabolite, which in turn acts as an analgesic. This study aimed to investigate the impact of CYP2D6 genotype on the analgesic effect of tramadol in clinical practice. A retrospective cohort study was performed in patients treated with tramadol for postoperative pain after arthroscopic surgery for rotator cuff injury during April 2017-March 2019. The impact of CYP2D6 genotypes on the analgesic effects was assessed by the numeric rating scale (NRS) pain scoring and analyzed by the Mann-Whitney U test. Stepwise multiple linear regression analysis was performed to identify predictive factors for the area under the time-NRS curve (NRS-AUC), which was calculated using the linear trapezoidal method. Among the 85 enrolled Japanese patients, the number of phenotypes with CYP2D6 normal metabolizer (NM) and intermediate metabolizer (IM) was n = 69 (81.1%) and n = 16 (18.9%), respectively. The NRS and NRS-AUC in the IM group were significantly higher than those in the NM group until Day 7 (p < 0.05). The multiple linear regression analysis indicated that the CYP2D6 polymorphism was a prediction factor of the high NRS-AUC levels in Days 0-7 (ß = 9.52, 95% CI 1.30-17.7). In IM patients, the analgesic effect of tramadol was significantly reduced one week after orthopedic surgery in clinical practice. Therefore, dose escalation of tramadol or the use of alternative analgesic medications can be recommended for IM patients.

Asymmetric Total Synthesis of Brasiliquinones B and C via Oxidative Cyclization of a Hydroquinone-Silyl Enol Ether Hybrid.

The asymmetric total synthesis of angucycline antibiotics (S)-brasiliquinones B and C was accomplished. The benz[a]anthraquinone core was constructed via oxidative cyclization of a hydroquinone-silyl enol ether hybrid. The resultant pentacyclic acetal was converted to the silyl enol ether, which was treated with Pd(II)/O2 to afford brasiliquinone C, after multistep conversion including dehydrogenation, desilylation and deacetalization, and hydroquinone oxidation. The (S)-configuration of natural brasiliquinones was confirmed based on the stereochemical correlation with the synthetic products.

First-in-Human Phase 1 Study of MORAb-202, an Antibody-Drug Conjugate Comprising Farletuzumab Linked to Eribulin Mesylate, in Patients with Folate Receptor-α-Positive Advanced Solid Tumors.

PURPOSE: MORAb-202, an antibody-drug conjugate containing farletuzumab and eribulin with a cathepsin-B cleavable linker, targets folate receptor α (FRα)-expressing tumor cells. The primary objective of this first-in-human study was to evaluate the safety and tolerability of MORAb-202 in patients with solid tumors. PATIENTS AND METHODS: Patients ≥20 years with adequate organ function and FRα-positive solid tumors who failed to respond to standard therapy were eligible. Patients received MORAb-202 intravenously at doses of 0.3 to 1.2 mg/kg once every three weeks. Endpoints included dose-limiting toxicities, safety, tumor responses, pharmacokinetics, and pharmacodynamics. TRIAL REGISTRATION NUMBER: NCT03386942 (ClinicalTrials.gov). RESULTS: Between November 28, 2017 and June 4, 2019, 22 patients (median age, 58.0 years) with advanced solid tumors were enrolled. Treatment-emergent adverse events occurred in 21 (95%) patients, with leukopenia and neutropenia in 10 (45%) patients each. One patient (0.9 mg/kg cohort) experienced two grade 3 dose-limiting toxicities: serum alanine aminotransferase and γ-glutamyl transferase increases. Following review by an independent adjudication committee, grade 1/2 interstitial lung disease thought to be related to MORAb-202 was identified in five (23%) patients. Complete response, partial response, and stable disease were observed in one, nine, and eight patients, respectively. The normalized predose serum FRα tended to be positively correlated with the maximum tumor shrinkage (R 2 = 0.2379; P = 0.0291). CONCLUSIONS: The MTD of MORAb-202 was not reached. MORAb-202 demonstrated promising antitumor activity in FRα-positive solid tumors and was generally well-tolerated at the tested doses. Further investigations are required to establish appropriate dosage and clinical utility of MORAb-202.

Phase 2 study of lenvatinib monotherapy as second-line treatment in unresectable biliary tract cancer: primary analysis results.

BACKGROUND: Biliary tract cancer (BTC) has a poor prognosis and lacks a standardized second-line therapy. Vascular endothelial growth factor (VEGF), fibroblast growth factor receptor (FGFR) 4, and platelet-derived growth factor receptor (PDGFR) are highly expressed in BTC. Therefore, lenvatinib (a known inhibitor of VEGF receptors 1-3, FGFRs 1-4, and PDGFR-α) was evaluated for second-line treatment of BTC. METHODS: In this single-arm, multicenter, open-label, phase 2 study, patients with BTC received lenvatinib 24 mg orally once daily in 28-day cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), PFS rate at 12 weeks, disease control rate, clinical benefit rate, safety and pharmacokinetic profiles. RESULTS: Twenty-six Japanese patients were enrolled and treated; 3 had a confirmed partial response per investigator assessment and per independent imaging review (IIR); ORR was 11.5% (90% confidence interval [CI]: 3.2-27.2). Median PFS was 3.19 months (95% CI: 2.79-7.23) per investigator assessment and 1.64 months (95% CI: 1.41-3.19) per IIR. Median OS was 7.35 months (95% CI: 4.50-11.27). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 21 patients (80.8%) and included hypertension (n = 10 [38.5%]), proteinuria (n = 3 [11.5%]), palmar-plantar erythrodysesthesia (n = 3 [11.5%]), decreased appetite (n = 3 [11.5%]), and anemia (n = 3 [11.5%]). Two deaths occurred due to TEAEs between treatment initiation and 30 days after last dose, but neither were considered treatment related. CONCLUSIONS: Lenvatinib demonstrated antitumor activity in BTC, with a tolerable safety profile, and should be further evaluated as potential second-line therapy for this difficult to treat population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02579616 . Date of registration: October 19, 2015.

A phase I study of ontuxizumab, a humanized monoclonal antibody targeting endosialin, in Japanese patients with solid tumors.

Background We conducted a first-in-Japanese, phase I study of ontuxizumab, a humanized, anti-endosialin monoclonal antibody, to confirm its tolerability, safety, and pharmacokinetics, and identify exploratory efficacy. Methods This was a multicenter, multiple-dose, open-label study in Japanese patients aged ≥20 years with solid tumors, including gastric cancer (GC) or advanced hepatocellular carcinoma (HCC), who had failed standard chemotherapy. The study comprised two parts: part 1 (dose-escalation; ontuxizumab 2-12 mg/kg weekly) and part 2 (cohort-expansion; 4 or 8 mg/kg weekly, or 12 mg/kg biweekly). Results Fifteen patients were treated in part 1, and 31 in part 2 (16 patients with GC and 15 with HCC). In part 1, the most common treatment-related, treatment-emergent adverse event (TEAE) was fatigue (20%); no patients had grade ≥ 3 treatment-related TEAEs. In part 2, the most common treatment-related TEAEs were constipation, malaise, hiccups, and increased bilirubin; treatment-related grade 3 TEAEs occurred in two patients with HCC. In part 1, no patients achieved a partial response, and 6/15 (40%) had stable disease (SD). In part 2, 2/15 patients (13.3%) with GC and 8/15 (53.3%) with HCC had SD. Tumor shrinkage was observed in 5/15 HCC patients (33.3%). Conclusions Ontuxizumab, up to a dosage of 12 mg/kg weekly, was generally safe and well tolerated in this population, with no dose-limiting toxicities. The maximum tolerated dose was not reached; 8 mg/kg weekly or 12 mg/kg biweekly were the recommended dosages. We observed long-term disease stabilization in GC and extraskeletal chondrosarcoma, and tumor shrinkage in gastrointestinal stromal tumor and HCC. Trial registration: NCT01773434 ( ClinicalTrials.gov ).

2-Aminoadipic Acid-C(O)-Glutamate Based Prostate-Specific Membrane Antigen Ligands for Potential Use as Theranostics.

The design and synthesis of prostate specific membrane antigen (PSMA) ligands derived from 2-aminoadipic acid, a building block that has not previously been used to construct PSMA ligands, are reported. The effects of both the linker length and of an N-substituent of our PSMA ligands were probed, and X-ray structures of five of these ligands bound to PSMA were obtained. Among the ligands disclosed herein, 13b showed the highest inhibitory activity for PSMA. As ligand 13b can readily be radiolabeled since its fluorine atom is adjacent to the nitrogen atom of its pyridine ring, the use of this and related compounds as theranostics can be pursued.

Use of a shoulder abduction brace after arthroscopic rotator cuff repair: A study on gait performance and falls.

BACKGROUND: Fall prevention is essential in patients after arthroscopic rotator cuff repair because of the high risk of re-rupture. However, there are no reports related to falls that occur during the early postoperative period, while the affected limb is immobilized. OBJECTIVES: This study assessed gait performance and falls in patients using a shoulder abduction brace after arthroscopic rotator cuff repair. STUDY DESIGN: Prospective cohort and postoperative repeated measures. METHODS: This study included 29 patients (mean age, 67.1 ± 7.4 years) who underwent arthroscopic rotator cuff repair followed by rehabilitation. The timed up and go test, Geriatric Depression Scale, and Falls Efficacy Scale were measured, and the numbers of falls were compared between those shoulder abduction brace users and patients who had undergone total hip or knee arthroplasty. RESULTS: In arthroscopic rotator cuff repair patients, there were significant improvements in timed up and go test and Geriatric Depression Scale, but no significant differences in Falls Efficacy Scale, between the second and fifth postoperative weeks ( p < 0.05). Additionally, arthroscopic rotator cuff repair patients fell more often than patients with total hip arthroplasty or total knee arthroplasty during the same period. CONCLUSION: The findings suggest that rehabilitation in arthroscopic rotator cuff repair patients is beneficial, but decreased gait performance due to the immobilizing shoulder abduction brace can lead to falls. Clinical relevance Although rehabilitation helps motor function and mental health after arthroscopic rotator cuff repair, shoulder abduction brace use is associated with impaired gait performance, high Falls Efficacy Scale scores, and risk of falls, so awareness of risk factors including medications and lower limb dysfunctions is especially important after arthroscopic rotator cuff repair.

Predicting the outcome of chronic kidney disease by the estimated nephron number: the rationale and design of PRONEP, a prospective, multicenter, observational cohort study.

BACKGROUND: The nephron number is thought to be associated with the outcome of chronic kidney disease (CKD). If the nephron number can be estimated in the clinical setting, it could become a strong tool to predict renal outcome. This study was designed to estimate the nephron number in CKD patients and to establish a method to predict the outcome by using the estimated nephron number. METHODS/DESIGN: The hypothesis of this study is that the estimated nephron number can predict the outcome of a CKD patient. This will be a multicenter, prospective (minimum 3 and maximum 5 years follow-up) study. The subjects will comprise CKD patients aged over 14 years who have undergone a kidney biopsy. From January 2011 to March 2013, we will recruit 600 CKD patients from 10 hospitals belonging to the National Hospital Organization of Japan. The primary parameter for assessment is the composite of total mortality, renal death, cerebro-cardiovascular events, and a 50% reduction in the eGFR. The secondary parameter is the rate of eGFR decline per year. The nephron number will be estimated by the glomerular density in biopsy specimens and the renal cortex volume. This study includes one sub-cohort study to establish the equation to calculate the renal cortex volume. Enrollment will be performed at the time of the kidney biopsy, and the data will consist of a medical interview, ultrasound for measurement of the kidney size, blood or urine test, and the pathological findings of the kidney biopsy. Patients will continue to have medical consultations and receive examinations and/or treatment as usual. The data from the patients will be collected once a year after the kidney biopsy until March 2016. All data using this study are easily obtained in routine clinical practice. DISCUSSION: This study includes the first trials to estimate the renal cortex volume and nephron number in the general clinical setting. Furthermore, this is the first prospective study to examine whether the nephron number predicts the outcome of CKD patients. The results from this study should provide powerful new tools for nephrologists in routine clinical practice. TRIAL REGISTRATION: UMIN-Clinical Trial Registration, UMIN000004784.

[S-1-based chemotherapy for unresectable advanced gastric cancer of the elderly or patients with renal dysfunction].

OBJECTIVE: S-1 based therapy is a valued standard chemotherapy regimen for unresectable gastric cancer in Japan. S-1/ CDDP therapy has been highly effective, especially for patients under 75 years old who have good organ function. However, it is the elderly and/or patients with renal dysfunction who make up the majority of the candidates for chemotherapy in general hospitals. These factors make it difficult to apply the results of RCTs to chemotherapy regimens. AIM AND METHODS: To investigate clinical outcomes, the medical records of patients who had received S-1 based chemotherapy for gastric cancer at our hospital from January 2002 to September 2009 were retrospectively reviewed. RESULTS: A total of 78 patients were evaluated for analyses. Among the patients, 23(29%)were the elderly, 8(10%)had renal dysfunction, and 27(35%)were either the elderly or those who had renal dysfunction. S-1/CDDP therapy was provided for 63% of the patients. Regarding the outcomes from therapy, RR was 44%, mPFS was 5. 4 months, and MST was 10. 6 months. Regarding survival benefit for OS, the elderly, the intestinal type, and therapy with S-1 alone were considered to be good factors in multi-variant analysis, but no significant differences were confirmed. CONCLUSION: In general practice, the elderly and/or patients with renal dysfunction account for 35%, and S-1-based chemotherapy has been proven to be very effective. However, additional effects of CDDP were not shown in this study.

Effects of HSP70 on the compression force-induced TNF-α and RANKL expression in human periodontal ligament cells.

OBJECTIVE AND DESIGN: The aim of this study was to investigate the effect of heat shock protein 70 (HSP70) on the mRNA expression of tumor necrosis factor-alpha (TNF-α) and receptor activator of nuclear factor-kappa B ligand (RANKL) induced by compressive forces (CF) in human periodontal ligament (hPDL) cells. MATERIAL AND TREATMENT: hPDL cells were subjected to 1.0, 2.0, or 4.0 g/cm(2) of CF for 24 h, and were treated with recombinant human inducible HSP70 for 12 h. METHODS: The mRNA expression of HSP27, HSP70, HSP90, TNF-α, RANKL and OPG from hPDL cells subjected to CF was determined by real-time PCR. The protein production of HSP70 was determined by Western blot analysis and ELISA. RESULTS: The mRNA expression of HSP70, TNF-α and RANKL were found to be increased in a time- and magnitude-dependent manner, detectable at 12, 9, and 9 h, respectively. TNF-α and RANKL expression gradually decreased at 12 h with increasing HSP70 levels, and further decreased thereafter. Furthermore, exogenous HSP70 partially inhibited the CF-induced TNF-α and RANKL expression in a dose-dependent manner at 6 and 12 h. CONCLUSIONS: These results indicate that HSP70 may modulate the mRNA expression of TNF-α and RANKL in hPDL cells in response to CF.

Peer standing and substance use in early-adolescent grade-level networks: a short-term longitudinal study.

Two competing hypotheses were tested concerning the associations between current alcohol and cigarette use and measures of individual, group and network peer standing in an ethnically-diverse sample of 156 male and female adolescents sampled at two time points in the seventh grade. Findings lent greater support to the person hypothesis, with early regular substance users enjoying elevated standing amongst their peers and maintaining this standing regardless of their maintenance of or desistance from current use later in the school year. In the fall semester, users (n=20, 13%) had greater social impact, were described by their peers as more popular, and were more central to the peer network than abstainers (i.e., those who did not report current use).Conversely, in the spring semester, there were no differences between users (n=22, 13%) and abstainers in peer ratings of popularity or social impact. Notably, the spring semester users group retained fewer than half of the users from the fall semester. Further, students who had reported current use in the fall, as a group, retained their positions of elevated peer standing in the spring, compared to all other students, and continued to be rated by their peers as more popular and as having greater social impact. We discuss the findings in terms of the benefit of employing simultaneous systemic and individual measures of peer standing or group prominence, which in the case of peer-based prevention programs, can help clarify the truly influential from the "pretenders" in the case of diffusion of risk-related behaviors.

Protection from inactivation of the adenine nucleotide translocator during hypoglycaemia-induced apoptosis by mitochondrial phospholipid hydroperoxide glutathione peroxidase.

We demonstrated that mitochondrial phospholipid hydroperoxide glutathione peroxidase (PHGPx) first suppressed the dissociation of cytochrome c (cyt c) from cardiolipin (CL) in mitochondrial inner membranes and then apoptosis caused by the hypoglycaemia by the prevention of peroxidation of CL [Nomura, Imai, Koumura, Arai and Nakagawa (1999) J. Biol. Chem. 274, 29294-29302; Nomura, Imai, Koumura, Kobayashi and Nakagawa (2000) Biochem. J. 351, 183-193]. The present study shows the involvement of peroxidation of CL in the inactivation of adenine nucleotide translocator (ANT) and the opening of permeability transition pores by using the system of ANT-reconstituted liposome and isolated mitochondria. ANT activity appeared in dioleoyl phosphatidylcholine proteoliposome containing 10% (mol/mol) CL or phosphatidylglycerol (PG), but not other classes of phospholipids. ANT activity was competitively inhibited by the addition of cardiolipin hydroperoxide (CLOOH) in reconstituted liposomes containing CL. However, phosphatidylcholine hydroperoxide failed to inactivate the activity of ANT. The activity of ANT in reconstituted liposomes, including CLOOH, recovered when CLOOH in reconstituted liposome was reduced to hydroxycardiolipin by incubation with PHGPx. The activity of ANT was determined in rat basophil leukaemia RBL2H3 cells after their exposure to 2-deoxyglucose. ANT activity decreased to 50% of the control level by 4 h in response to apoptosis. In parallel, cyt c and apoptosis-inducing factor (AIF) were released from mitochondria. Suppression of the accumulation of CLOOH by overexpression of PHGPx in mitochondria effectively prevented the inactivation of ANT, the opening of permeability transition pores and the release of cyt c and AIF from mitochondria in hypoglycaemia-induced apoptotic cells. These findings suggest that mitochondrial PHGPx might be involved in the modulation of the activity of ANT and the opening of pores for the release of cyt c via the modulation of levels of CLOOH in the mitochondria.