The Uridylyl Transferase TUT7-Mediated Accumulation of Exosomal miR-1246 Reprograms TAMs to Support CRC Progression.

Tumor-associated macrophages (TAMs) play a crucial role in promoting tumor growth and dissemination, motivating a search for key targets to interfere with the activation of TAMs or reprogram TAMs into the tumor-suppressive type. To gain insight into the mechanisms of macrophage polarization, a designed co-culture system is established, allowing for the education of macrophages in a manner that closely mimics the intricacies of TAMs in the tumor immune microenvironment (TIME). Through database mining, exosomal miR-1246 is identified and is then validated. Exosomal miR-1246-driven polarization of TAMs disrupts the infiltration and function of CD8+ T cells. Mechanically, the amassment of exosomal miR-1246 stems from TUT7-mediated degradation of small noncoding RNA, a process stabilized by SNRPB, but not the precursor of miR-1246. Moreover, an Exo-motif is present in the exosomal miR-1246 sequence, enabling it to bind with the exosomal sorting protein hnRNPA2B1. RNA-seq analysis reveals that exogenous miR-1246 modulates the polarization of TAMs at a post-transcriptional level, emphasizing the pivotal role of the NLRP3 in macrophage polarization. In conclusion, the findings underscore the importance of exosomal miR-1246 as a trigger of macrophage reprogramming and uncover a novel mechanism for its enhanced presence in the TIME.

Automatic Registration of Homogeneous and Cross-Source TomoSAR Point Clouds in Urban Areas.

Building reconstruction using high-resolution satellite-based synthetic SAR tomography (TomoSAR) is of great importance in urban planning and city modeling applications. However, since the imaging mode of SAR is side-by-side, the TomoSAR point cloud of a single orbit cannot achieve a complete observation of buildings. It is difficult for existing methods to extract the same features, as well as to use the overlap rate to achieve the alignment of the homologous TomoSAR point cloud and the cross-source TomoSAR point cloud. Therefore, this paper proposes a robust alignment method for TomoSAR point clouds in urban areas. First, noise points and outlier points are filtered by statistical filtering, and density of projection point (DoPP)-based projection is used to extract TomoSAR building point clouds and obtain the facade points for subsequent calculations based on density clustering. Subsequently, coarse alignment of source and target point clouds was performed using principal component analysis (PCA). Lastly, the rotation and translation coefficients were calculated using the angle of the normal vector of the opposite facade of the building and the distance of the outer end of the facade projection. The experimental results verify the feasibility and robustness of the proposed method. For the homologous TomoSAR point cloud, the experimental results show that the average rotation error of the proposed method was less than 0.1°, and the average translation error was less than 0.25 m. The alignment accuracy of the cross-source TomoSAR point cloud was evaluated for the defined angle and distance, whose values were less than 0.2° and 0.25 m.

Knockouts of TUT7 and 3'hExo show that they cooperate in histone mRNA maintenance and degradation.

Metazoan histone mRNAs are the only cellular eukaryotic mRNAs that are not polyadenylated, ending instead in a conserved stem-loop. SLBP is bound to the 3' end of histone mRNAs and is required for translation of histone mRNA. The expression of histone mRNAs is tightly cell-cycle regulated. A major regulatory step is rapid degradation of histone mRNA at the end of S-phase or when DNA synthesis is inhibited in S-phase. 3'hExo, a 3' to 5' exonuclease, binds to the SLBP/SL complex and trims histone mRNA to 3 nt after the stem-loop. Together with a terminal uridyl transferase, 3'hExo maintains the length of the histone mRNA during S-phase. 3'hExo is essential for initiating histone mRNA degradation on polyribosomes, initiating degradation into the 3' side of the stem-loop. There is extensive uridylation of degradation intermediates in the 3' side of the stem when histone mRNA is degraded. Here, we knocked out TUT7 and 3'hExo and we show that both modification of histone mRNA during S-phase and degradation of histone mRNA involve the interaction of 3'hExo, and a specific TUTase, TENT3B (TUT7, ZCCHC6). Knockout of 3'hExo prevents the initiation of 3' to 5' degradation, stabilizing histone mRNA, whereas knockout of TUT7 prevents uridylation of the mRNA degradation intermediates, slowing the rate of degradation. In synchronized 3'hExo KO cells, histone mRNA degradation is delayed, but the histone mRNA is degraded prior to mitosis by a different pathway.

Joint Sparsity for TomoSAR Imaging in Urban Areas Using Building POI and TerraSAR-X Staring Spotlight Data.

Synthetic aperture radar (SAR) tomography (TomoSAR) can obtain 3D imaging models of observed urban areas and can also discriminate different scatters in an azimuth-range pixel unit. Recently, compressive sensing (CS) has been applied to TomoSAR imaging with the use of very-high-resolution (VHR) SAR images delivered by modern SAR systems, such as TerraSAR-X and TanDEM-X. Compared with the traditional Fourier transform and spectrum estimation methods, using sparse information for TomoSAR imaging can obtain super-resolution power and robustness and is only minorly impacted by the sidelobe effect. However, due to the tight control of SAR satellite orbit, the number of acquisitions is usually too low to form a synthetic aperture in the elevation direction, and the baseline distribution of acquisitions is also uneven. In addition, artificial outliers may easily be generated in later TomoSAR processing, leading to a poor mapping product. Focusing on these problems, by synthesizing the opinions of various experts and scholarly works, this paper briefly reviews the research status of sparse TomoSAR imaging. Then, a joint sparse imaging algorithm, based on the building points of interest (POIs) and maximum likelihood estimation, is proposed to reduce the number of acquisitions required and reject the scatterer outliers. Moreover, we adopted the proposed novel workflow in the TerraSAR-X datasets in staring spotlight (ST) work mode. The experiments on simulation data and TerraSAR-X data stacks not only indicated the effectiveness of the proposed approach, but also proved the great potential of producing a high-precision dense point cloud from staring spotlight (ST) data.

Underlying Topography Inversion Using Dual Polarimetric TomoSAR.

Underlying topography plays an important role in the national economic construction, military security, resource exploration and investigation. Since synthetic aperture radar tomography (TomoSAR) can achieve the three-dimensional imaging of forests, it has been widely used in underlying topography estimation. At present, there are two kinds of TomoSAR based on the applied datasets: single polarimetric TomoSAR (SP-TomoSAR) and fully polarimetric TomoSAR (FP-TomoSAR). However, SP-TomoSAR cannot obtain the underlying topography accurately due to the lack of enough observations. FP-TomoSAR can improve the estimation accuracy of underlying topography. However, it requires high-cost data acquisition for the large-scale application. Thus, this paper proposes the dual polarimetric TomoSAR (DP-TomoSAR) as another suitable candidate to estimate the underlying topography because of its wide swath and multiple polarimetric observations. Moreover, three frequently used spectral estimation algorithms, namely, Beamforming, Capon and MUSIC, are used in DP-TomoSAR. For validation, a series of simulated experiments was carried out, and the airborne P-band multiple polarimetric SAR data over the Lope, Gabon was also acquired to estimate the underlying topography. The results suggest that DP-TomoSAR in HH & HV combination is more suitable to estimate underlying topography over forest areas than other DP combinations. Moreover, the estimation accuracy of DP-TomoSAR is slightly lower than that of FP-TomoSAR but is higher than that of SP-TomoSAR.

A model study for constructing the DEF-benzoxocin ring system of menogaril and nogalamycin via a reductive Heck cyclization.

A novel reductive Heck cyclization approach was developed in order to construct a model DEF-benzoxocin ring system that is present in nogalamycin, menogaril, and related anthracycline antitumor antibiotics.

Phase II evaluation of menogaril in advanced prostate cancer: Eastern Cooperative Oncology Group EST P-A885.

Menogaril is a semisynthetic anthracycline that is less cardiotoxic than doxorubicin in a preclinical model. We conducted a phase II trial to determine the activity of menogaril in hormone-refractory prostate cancer. Between October 1985 and November 1987, 32 eligible patients were enrolled and were divided into good- and poor-risk categories, the latter being defined by prior radiotherapy to less than one third of the marrow-containing skeleton. Good-risk patients received a starting dose of 200 mg/m2 by 60-minute IV infusion, whereas the poor-risk patients received 160 mg/m2. Treatment was repeated every 3 weeks until disease progression. Menogaril caused leukopenia in 90% of patients, of whom 47% had grade III or IV toxicity. Thrombocytopenia was uncommon and mild, with only three patients (9%) experiencing grade II toxicity. Nonhematologic toxicity included mucositis (9%), and mild weight loss in 33% of patients. Nine patients (28%) had stable disease of 3 or more months' duration. There were no objective partial or complete responses. The median time to progression for the entire group was 10 weeks, and the median survival time for all patients was 24 weeks. Because of appreciable toxicity and limited antitumor activity, further study of menogaril cannot be recommended in hormone-refractory prostate cancer.

Phase II trial of menogaril in patients with previously treated multiple myeloma or chronic lymphocytic leukemia.

Menogaril is a semisynthetic anthracycline with relative lack of cardiotoxicity. Ten patients with multiple myeloma (MM), seven patients with chronic lymphocytic leukemia (CLL), and one patient with diffuse well-differentiated lymphocytic lymphoma (DWDL) were treated with menogaril, 160 mg/m2 (for MM) or 200 mg/m2 (for CLL/DWDL), given as a 2-hour intravenous infusion, repeated every 28 days. All patients except one with CLL had been previously treated with one chemotherapy regimen and had either not responded or had relapsed after a response to prior treatment. There were no objective responses to treatment. Among the six evaluable patients with MM, two had stable disease with subjective improvement in symptoms for five to 25 cycles, and among the eight patients with CLL/DWDL, five patients remained stable for two to eight cycles on treatment. The remainder of the patients had progressive disease after one to two cycles of chemotherapy. Five grade 4 hematologic toxicities were observed. There was one fatal neutropenic sepsis. Menogaril, as administered in this study, does not appear to have significant activity in patients with previously treated MM or CLL.

Response and progression in recurrent malignant glioma.

In this article we report the results of a study of the relationship between response and progression in 375 patients with recurrent glioma enrolled in phase II chemotherapy trials. We reviewed the records of patients from 8 consecutive phase II trials, including 225 patients with recurrent glioblastoma multiforme and 150 with recurrent anaplastic astrocytoma. Median age was 45 years (range, 15-82) and median Karnofsky performance score was 80 (range, 60-100). Forty-one patients (11%) had more than two prior resections and/or more than two prior chemotherapy regimens. Best response was complete (n = 1) or partial (n = 33) in 34 patients (9%). Median time to response was 14 weeks, and median response duration was 44 weeks. Simon-Makuch estimates for 52-week progression-free survival for patients progression-free at 13 weeks were 48% for response and 28% for nonresponse. When response was treated as a time-dependent covariate in a Cox proportional hazards regression analysis, response was associated with significantly lower failure rates (hazard ratio 0.5; 95% confidence interval 0.3-0.8; P = 0.0016). This study showed that response in recurrent glioma is associated with a significant reduction in progression rates.

Phase II trial of menogaril in non-Hodgkin's lymphomas: a Southwest Oncology Group trial.

PURPOSE: To assess the efficacy and toxicity of menogaril against non-Hodgkin's lymphoma (NHL) in a group of previously treated patients. PATIENTS AND METHODS: Sixty-two eligible patients with a histologic diagnosis of NHL were enrolled, 35 of who had intermediate or high-grade histologies and 27 of who had low-grade lymphomas. Patients with intermediate or high-grade lymphomas had received only 1 prior chemotherapy regimen, while patients with low-grade histologies had received 1 or 2 prior chemotherapy regimens. Menogaril was administered at 160 mg/m2 intravenously over 1 hour, once every 28 days. RESULTS: Among the 35 patients with intermediate or high-grade lymphomas who were evaluable for response, 6 of 35 patients achieved a partial response (PR) for a response rate of 17% (95% confidence interval: 7%-34%). Median survival in this group of patients was 13 months. For those patients with low-grade lymphoma, 5 of 26 patients achieved a PR for a response rate of 19% (95% confidence interval: 6%-38%). No complete responses were observed in either patient group. The incidence of serious (grade 3 or 4) toxicity for those with intermediate/high-grade and low-grade lymphomas was 43% and 44%, respectively. Most of these toxic effects consisted of reversible myelosuppression. Menogaril was discontinued in 2 patients due to prolonged neutropenia. Cardiotoxicity was observed in 4 patients, requiring discontinuation of the drug in 1 patient. No treatment-related deaths occurred and the overall toxicity was felt to be acceptable. CONCLUSION: The observed antitumor activity of single agent menogaril against both intermediate/high-grade and low-grade lymphomas was modest. Further exploration of this agent in patients with non-Hodgkin's lymphomas does not seem warranted.

New agents in the treatment of small cell lung cancer.

The treatment of small cell lung cancer (SCLC) has evolved significantly over the past 3 decades. Single-agent and combination chemotherapies given with radiotherapy have greatly improved response rates and median survival. Combination regimens such as cisplatin/etoposide, carboplatin/etoposide, ifosfamide/carboplatin/etoposide, cyclophosphamide/doxorubicin/vincristine, and etoposide/ifosfamide/cisplatin have all achieved good response rates. Improving long-term survival, however, has remained problematic. Treatment with biological response modifiers (interferons alpha and gamma) has not shown promise in this setting. New agents showing good preliminary single-agent activity in untreated SCLC include paclitaxel, vinorelbine, gemcitabine, topotecan, and teniposide. Results obtained with single-agent docetaxel and CPT-11 are thus far inconclusive. Studies evaluating response and survival rates of these new agents in combination with agents of known activity are underway.

Differential poisoning of topoisomerases by menogaril and nogalamycin dictated by the minor groove-binding nogalose sugar.

The effect of DNA binding on poisoning of human DNA TOP1 has been studied using a pair of related anthracyclines which differ only by a nogalose sugar ring. We show that the nogalose sugar ring of nogalamycin, which binds to the minor groove of DNA, plays an important role in affecting topoisomerase-specific poisoning. Using purified mammalian topoisomerases, menogaril is shown to poison topoisomerase II but not topoisomerase I. By contrast, nogalamycin poisons topoisomerase I but not topoisomerase II. Consistent with the biochemical studies, CEM/VM-1 cells which express drug-resistant TOP2alpha are cross-resistant to menogaril but not nogalamycin. The mechanism by which nogalamycin poisons topoisomerase I has been studied by analyzing a major topoisomerase I-mediated DNA cleavage site induced by nogalamycin. This site is mapped to a sequence embedded in an AT-rich region with four scattered GC base pairs (bps) (at -10, -6, +2, and +12 positions). GC bps embedded in AT-rich regions are known to be essential for nogalamycin binding. Surprisingly, DNase I footprinting analysis of nogalamycin-DNA complexes has revealed a drug-free region from -2 to +9 encompassing the major cleavage site. Our results suggest that nogalamycin, in contrast to camptothecin, may stimulate TOP1 cleavage by binding to a site(s) distal to the site of cleavage.

[TUT-7 early phase II clinical study for various solid tumors and hematologic malignancies].

An early Phase II study with TUT-7 (menogaril), a new anthracycline antitumor antibiotic, was conducted in patients with various malignant tumors at 81 departments of 65 institutions nationwide. One course of TUT-7 treatment consisted of seven (7) or fourteen (14) consecutive days of administration at 75 or 100 mg/body/day with two-week drug withdrawal; at least two courses of treatment were given in principle. Among the 165 patients registered, 145 patients were eligible and 128 patients were evaluable for antitumor efficacy. In 11 patients with malignant lymphoma, one (1) had CR and five (5) had PR (54.5%); in three (3) patients with prostate cancer, one (1) had PR (33.3%); and in 12 patients with uterine cervical cancer, two (2) had PR (16.7%). Adverse drug reactions frequently observed were digestive organ disorders (anorexia and nausea/vomiting) and malaise. The abnormality in laboratory tests observed frequently was myelosuppression (leukopenia and neutropenia).

[Menogaril (TUT-7) late phase II study for malignant lymphoma, adult T-cell leukemia and lymphoma (ATLL)].

A late Phase II multicenter study with menogaril was conducted nationwide in patients with malignant lymphoma [non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD)], and ATLL, menogaril was orally administered at 100 mg daily after breakfast, for seven consecutive days with two- or three-week drug withdrawal, then menogaril administration was repeated. For malignant lymphoma, in 81 patients with NHL and 5 patients with HD registered, 70 and 5 patients were evaluable for efficacy, respectively. The efficacy rates were 32.9% (6 CRs + 17 PRs/70) for NHL and 20.0% (1 PR/5) for HD, respectively; that for the NHL patients with prior anthracycline antibiotic chemotherapy was 30.5% (5 CRs and 13 PRs/59). For ATLL, among the 16 patients registered, 15 were evaluable for efficacy, and the efficacy rate was 40.0% (2 CRs and 4 PRs/15). Adverse drug reactions frequently observed in the patients with malignant lymphoma and ATLL included bone-marrow suppression and gastrointestinal symptoms such as anorexia, and nausea/vomiting. With these results, menogaril was considered to be effective for the treatment of non-Hodgkin's lymphoma and ATLL.

[TUT-7 phase I clinical study. TUT-7 Study Group].

A phase I study with TUT-7, a new anthracycline antitumor antibiotic, was conducted in 35 malignant tumor patients at 11 institutions nationwide. The study was initiated with a single dose at 100 mg/body which was equivalent to 2n, then the dose as escalated up to 700 mg/body in accordance with the modified Fibonacci's scheme. The dose limiting factor (DLF) was considered to be leukopenia, and maximum tolerated dose (MTD) was 700 mg/ body. The consecutive days dosing study subsequently conducted started with 25 mg/body/day, and the dose level was escalated up to 150 mg /body/day. TUT-7 was orally administered for seven (7) to fourteen (14) consecutive days in principle. It was considered that DLF was leukopenia and MTD was 100 mg/body/day for consecutive days dosing. The study indicated that serum drug concentrations reached their plateaus on the 5th day after initiation of TUT-7 treatment and the accumulation of this compound was low. With these findings, a regimen with a dose of 100 mg/body/day orally administered for 14 consecutive days was recommended for early phase II studies.

Activity of menogaril against various malignant lymphoma cell lines and a human lymphoma xenograft in mice.

Menogaril is an antitumor agent different from other anthracyclines in that it is active after oral administration; therefore, extravasation is not a side effect. In this basic study, we examined the antitumor activity of menogaril against malignant lymphoma. We compared its activity towards experimental malignant lymphoma with that of Adriamycin, epirubicin, pirarubicin, vincristine, and etoposide, treating mice with each drug at the dose schedule usually used for patients. Menogaril rapidly penetrated lymphoma cells and remained there at least 3 hours after the drug was washed out. Menogaril cleaved more double-stranded DNA in lymphoma cells than Adriamycin, epirubicin, pirarubicin, or etoposide. Menogaril had stronger antitumor activity against experimental malignant lymphoma in mice than Adriamycin, epirubicin, vincristine, and etoposide. Menogaril significantly lengthened the life span of mice bearing one of three lymphoma cell lines resistant to cisplatin, vincristine, or cyclophosphamide. Menogaril had stronger antitumor activity against the human malignant lymphoma xenograft LM-3 than Adriamycin. The strength of the cytotoxic activity of Menogaril might arise from its ready penetration into cells and its cleavage of double-stranded DNA. Therefore, Menogaril might become a useful drug for the treatment of patients with malignant lymphoma by oral administration; 7 days of administration was effective in the in vivo experiments.

Prediction of the optimum clinical dosing schedule for menogaril from results with tumor-bearing mice.

Menogaril is an antitumor agent active after oral administration, and unlike other anthracyclines, extravasation cannot occur. When the IC90 values of menogaril were plotted versus exposure time on a double-logarithmic scale, the regression lines had slopes between -0.64 and -0.80. These results showed that the mode of action of menogaril was type lb, dependent on the area under the curve (AUC) of concentration versus time, like Adriamycin. In calculations that simulated pharmacokinetic findings if administration were for three consecutive days (the single dose given was 79 mg/kg) or on days 1 and 8 (the single dose was 238 mg/kg), the peak tumor concentration of menogaril was 1870 and 2985 ng/g and the AUC was 68,363 and 89,352 ng/g hour, respectively. Of the dosing schedules tried, these two dosing schedules were the optimum, with satisfactory antitumor activity against mouse solid tumor Colon 26 and with a wide range of effective dose concentrations. Since menogaril was AUC-dependent, it was possible to predict antitumor activity and to choose optimum dosing schedules on the basis of cell-kill kinetic and pharmacokinetic information.

Antitumor activity of menogaril alone, and in combination against human mammary cancer models in mice and rats.

Menogaril is an antitumor agent different from other anthracyclines in being active after oral administration. To predict its clinical effectiveness by this route against human breast cancer, we compared its antitumor activity against breast cancer in experimental animals with that of injected Adriamycin. Menogaril had half the much antitumor activity of Adriamycin against human mammary cancer cell lines. Menogaril given orally also had a antitumor activity against mammary cancer caused by 7,12-dimethyl-benz[a]anthracene in rats comparable with that of Adriamycin. The high concentration of menogaril in tumor tissue seemed to contribute to its effectiveness. Of several combinations of cyclophosphamide, Adriamycin, menogaril, and 5-fluorouracil, the combination of cyclophosphamide, menogaril, and 5-fluorouracil was most effective against mouse leukemia L1210 and human breast cancer xenografts in mice. This combination might have antitumor activity against breast cancer superior to that of the therapy currently of first choice (cyclophosphamide, Adriamycin, and 5-fluorouracil) in the clinic.

A phase II study of menogaril (7R-O-methylnogarol) in patients with relapsed/refractory acute myeloid leukemia: a study of the Eastern Cooperative Oncology Group.

Fifty-one patients (47 evaluable) with AML, 27 in first relapse and 20 either in second relapse or refractory were treated with menogaril, 100 mg/m2/day as a 90-min infusion daily for 5 days. The complete response (CR) rate was 17% (8/47), and there was one partial response. Seven of eight responders were in first relapse with a 26% response rate among first relapse patients (7/27). The median duration of survival was 3 months for all first relapse patients and 4.3 months for all other patients. Toxicity included grades 3-4 pancytopenia and fever (100% of patients) and grades 3-4 stomatitis and hepatic enzyme elevation (25% of patients). Grades 3-4 cardiac toxicity occurred in three patients (two grade 3 arrhythmias and one heart block). All had previously received anthracyclines. Remission duration was 1.6-48+ months; two patients underwent bone marrow transplantation and continue in CR at 36+ and 48+ months. The nontransplanted patients remained in CR 1.6, 2.0, 3, 7, 14 and 27 months. Activity and toxicity of menogaril in this study were comparable to that of other clinically useful anthracyclines in AML. Further investigation of this agent in AML is warranted.

Hepatocellular carcinoma. An ECOG randomized phase II study of beta-interferon and menogaril.

This study was undertaken to investigate the response rate, time to treatment failure and survival time of patients with hepatocellular cancer (HCC) treated with beta-interferon or menogaril. Sixty-nine patients with histologically confirmed, advanced, measurable hepatocellular carcinoma were randomized to receive beta-interferon or menogaril. Eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2, or 3, as well as adequate kidney and liver function and hematologic reserve. The number of patients with lethal, life-threatening, and severe toxicities on beta-interferon were 1, 3, and 12 and on menogaril 2, 5, and 10, respectively. No objective responses were documented among the 61 patients who had HCC, histologically reviewed and confirmed. The time to treatment failure was 6.7 weeks on beta-interferon and 8.6 weeks on menogaril. The median survival time was 11.1 weeks on beta-interferon and 23.1 weeks on menogaril (South African patients 10.1 weeks). The difference is not significant. Poor prognostic factors were jaundice, age, and associated hepatitis. After controlling for other covariates, beta-interferon appears to increase the relative risk of dying by 2.7. This trial reconfirms the importance, previously reported by ECOG of jaundice and age in the prognosis of patients with HCC. It shows that further trials with neither beta-interferon nor menogaril are warranted.