Chemical genetic screening identifies nalacin as an inhibitor of GH3 amido synthetase for auxin conjugation.

Auxin inactivation is critical for plant growth and development. To develop plant growth regulators functioning in auxin inactivation pathway, we performed a phenotype-based chemical screen in Arabidopsis and identified a chemical, nalacin, that partially mimicked the effects of auxin. Genetic, pharmacological, and biochemical approaches demonstrated that nalacin exerts its auxin-like activities by inhibiting indole-3-acetic acid (IAA) conjugation that is mediated by Gretchen Hagen 3 (GH3) acyl acid amido synthetases. The crystal structure of Arabidopsis GH3.6 in complex with D4 (a derivative of nalacin) together with docking simulation analysis revealed the molecular basis of the inhibition of group II GH3 by nalacin. Sequence alignment analysis indicated broad bioactivities of nalacin and D4 as inhibitors of GH3s in vascular plants, which were confirmed, at least, in tomato and rice. In summary, our work identifies nalacin as a potent inhibitor of IAA conjugation mediated by group II GH3 that plays versatile roles in hormone-regulated plant development and has potential applications in both basic research and agriculture.

Rational design of Striga hermonthica-specific seed germination inhibitors.

The obligate hemiparasitic weed Striga hermonthica grows on cereal roots and presents a severe threat to global food security by causing enormous yield losses, particularly in sub-Saharan Africa. The rapidly increasing Striga seed bank in infested soils provides a major obstacle in controlling this weed. Striga seeds require host-derived strigolactones (SLs) for germination, and corresponding antagonists could be used as germination inhibitors. Recently, we demonstrated that the common detergent Triton X-100 is a specific inhibitor of Striga seed germination by binding noncovalently to its receptor, S. hermonthica HYPO-SENSITIVE TO LIGHT 7 (ShHTL7), without blocking the rice (Oryza sativa) SL receptor DWARF14 (OsD14). Moreover, triazole ureas, the potent covalently binding antagonists of rice SL perception with much higher activity toward OsD14, showed inhibition of Striga but were less specific. Considering that Triton X-100 is not suitable for field application and by combining structural elements of Triton and triazole urea, we developed two hybrid compounds, KK023-N1 and KK023-N2, as potential Striga-specific germination inhibitors. Both compounds blocked the hydrolysis activity of ShHTL7 but did not affect that of OsD14. Binding of KK023-N1 diminished ShHTL7 interaction with S. hermonthica MORE AXILLARY BRANCHING 2, a major component in SL signal transduction, and increased ShHTL7 thermal specificity. Docking studies indicate that KK023-N1 binding is not covalent but is caused by hydrophobic interactions. Finally, in vitro and greenhouse tests revealed specific inhibition of Striga seed germination, which led to a 38% reduction in Striga infestation in pot experiments. These findings reveal that KK023-N1 is a potential candidate for combating Striga and a promising basis for rational design and development of further Striga-specific herbicides.

Function of hydroxycinnamoyl spermidines in seedling growth of Arabidopsis.

Hydroxycinnamic acid amides are involved in various developmental processes as well as in biotic and abiotic stress responses. Among them, the presence of spermidine derivatives, such as N1,N8-di(coumaroyl)-spermidine and N1,N8-di(sinapoyl)-spermidine, and their biosynthetic genes have been reported in Arabidopsis, but their functions in plants are still unknown. We chemically synthesized the above-mentioned spermidine derivatives to assess their physiological functions in Arabidopsis. We evaluated the growth and development of chemically treated Arabidopsis and demonstrated that these compounds inhibited seed germination, hypocotyl elongation, and primary root growth, which could be due to modulation of plant hormone homeostasis and signaling. The results suggest that these compounds are regulatory metabolites that modulate plant growth and development.

A phase II randomised study to evaluate the efficacy of aprepitant plus palonosetron for preventing delayed-phase CINV associated with TC therapy in gynaecological cancer.

AIM: Chemotherapy-induced nausea and vomiting (CINV) is one of the most frequently encountered side effects of cancer treatment. Severe CINV can lead patients to refuse chemotherapy, which ultimately affects cancer outcomes. The development of fairly new antiemetic agents, 5-hydroxytryptamine-3 receptor antagonists, palonosetron and neurokinin-1 receptor antagonists and aprepitant has reduced the risk and incidence of CINV. In this study, we assessed the efficacy of aprepitant plus palonosetron against palonosetron for CINV in patients receiving moderately emetic cancer chemotherapy (paclitaxel and carboplatin combination [TC] therapy). METHODS: Between November 2010 and March 2014, 78 patients with gynecological cancer treated with TC therapy were randomized into two groups: an aprepitant group (administered aprepitant, dexamethasone and palonosetron) and a control group (administered dexamethasone and palonosetron). The primary study endpoint was complete response, defined as the complete absence of emetic events in the delayed phase. RESULTS: The complete response rate in the delayed phase differed significantly between the two groups, with 82% in the aprepitant group and 97% in the control group (P = 0.025). CONCLUSION: The combination of aprepitant and palonosetron appears to be of greater efficacy than palonosetron alone for the prevention of delayed-phase CINV induced by TC therapy.

Long-term efficacy and safety of aromatase inhibitor use for leiomyomatosis peritonealis disseminata.

Leiomyomatosis peritonealis disseminata is a rare disease characterized by pelvic smooth-muscle nodules of various sizes. It is sometimes misdiagnosed as ovarian or peritoneal carcinoma metastasis; therefore, surgical excision for pathological diagnosis is required. Treatment options include bilateral salpingo-oophorectomy (BSO), gonadotrophin-releasing hormone agonist therapy, and aromatase inhibitor therapy. All of these suppress estrogen levels, but a standard treatment has not been established. A 40-year-old woman had multiple pelvic tumors, suspicious for ovarian cancer. She underwent laparotomy, where frozen sections of the nodules revealed leiomyomatosis peritonealis disseminata. After she completed gonadotrophin-releasing hormone agonist therapy, we performed a total abdominal hysterectomy and BSO with residual-nodule resection, but the nodules recurred 6 months after surgery. We then started letrozole, and 3 years have now elapsed without nodule enlargement or development of new lesions. The long-term use of aromatase inhibitor therapy is thought to be effective and safe for patients with recurrence after BSO.

Outcome of Neoadjuvant Intra-Arterial Chemotherapy and Radical Hysterectomy for Treatment of Bulky Stage IB to Stage IIB Uterine Cervical Cancer: Can Postoperative Irradiation Be Avoided?

OBJECTIVES: We evaluated whether our neoadjuvant intra-arterial chemotherapy (NAIC) effectively precludes the need for postoperative radiation therapy in patients treated by radical hysterectomy for IB2 to IIB cervical cancer. MATERIALS AND METHODS: Study subjects were 52 patients with a bulky cervical tumor diagnosed and treated at Juntendo University Hospital or Juntendo Nerima Hospital. The NAIC combined cisplatin, epirubicin, mitomycin-C, and 5-fluorouracil; and radical hysterectomy was to be performed after 2 cycles. The main variables analyzed were clinical and histologic response to NAIC, NAIC-related adverse events, adjuvant chemotherapies, relapse-free and overall survival, recurrence, and prognostic factors. RESULTS: Patients were judged eligible for radical hysterectomy, and 51 underwent the surgery. The overall positive response (complete response [CR] + partial response [PR]) to NAIC was 88.5%. Median follow-up time was 84 months (5-136 months). Three-year relapse-free survival and overall survival were 80.5% and 77.8%, respectively. The recurrence rate was 19.2% (10/52 patients). Seven (13.5%) of the 52 patients died from the disease during follow-up. Lymph node status (positive vs negative) and the histologic effect of NAIC (grades 0-1 vs grades 2-3) were shown to be prognostic factors (P = 0.024 and P = 0.021, respectively). CONCLUSIONS: Our NAIC strategy seems to be well tolerated and beneficial for patients with bulky IB2 to IIB cervical cancer. With this strategy, radiation therapy remains an option in cases of recurrence. For cases in which lymph node metastasis is found or the histologic effect of NAIC is low, our adjuvant chemotherapy regimen may need adjustment to improve prognosis.

Analysis of positron emission tomography/computed tomography in patients to differentiate between malignant transformation of endometrioma and endometrioma.

PURPOSE: Of those patients who undergo open surgery for a suspicion of malignant transformation of endometrioma (MTOE) due to solid nodule enhancement identified by contrast-enhanced magnetic resonance imaging (MRI), some benign endometrioma cases are included. The aim of this retrospective study was to determine the value and diagnostic accuracy of positron emission tomography/computed tomography (PET/CT) using 18-fluoro-2-deoxy-D-glucose (FDG) to differentiate between MTOE and endometrioma. PATIENTS AND METHODS: We retrospectively analyzed 1599 consecutive patients who underwent laparoscopic surgery for the diagnosis of endometrioma preoperatively and 31 patients who underwent open surgery for a suspicion of MTOE preoperatively from January 2003 to December 2011. We analyzed the age, serum CA125 levels, and MRI findings of the patients and calculated the optimal cut-off value for PET/CT using receiver operating characteristic curve analysis. RESULTS: Of the 1,599 patients who underwent laparoscopic surgery for a suspicion of endometrioma preoperatively, malignancy was identified in one (0.062 %) patient. Of the 31 patients who underwent open surgery for a suspicion of MTOE preoperatively, 11 were diagnosed with endometrioma (false positive group) and 20 with MTOE stage I (positive group). Age, tumor size, presence of shading on MRI and maximum standardized uptake values (SUVmax) on PET/CT were significantly different between the two groups. A SUVmax cut-off >4.0 is capable of excluding endometrioma cases, with 75 % sensitivity and 100 % specificity (area under the curve 90 %). CONCLUSION: PET/CT is a good diagnostic tool for MTOE using the optimal SUVmax cut-off of 4.0 (75 % sensitivity and 100 % specificity).

Fat embolism syndrome: A severe case diagnosed early using dual-energy CT and saved with VA-ECMO and inhaled nitric oxide.

Diagnosing FES is difficult and time-consuming, and identify FES as an etiology of right ventricular volume overload for early diagnosis. Because FES is a reversible condition, even severe cases can bse treated if the patient survives the acute phase.

Endoloop ligation technique for prolapsed pedunculated submucous uterine myoma: utility and reliability.

PURPOSE: We use a non-surgical endoloop snare technique to remove prolapsed pedunculated submucous uterine myomas under the concept that ligating the pedicle causes tumor necrosis and natural elimination of the tumor. We evaluated our method on the basis of clinical outcomes. METHODS: For pertinent clinical data, we reviewed the hospital records of 11 patients treated by our new method between July 2009 and 2010 and followed up for 22-31 months. RESULTS: Patients' mean age was 40.9 years, and the mean hemoglobin level was 10.6 g/dl. None required urgent hospitalization, blood transfusion, or laparotomy. The tumors were eliminated naturally or removed by cutting necrotic pedicle within 4-11 days. One patient required a second endoloop application. Another one patient required follow-up surgery for a second submucous myoma, adenomyosis, and persistent hypermenorrhea. CONCLUSIONS: Endoloop ligation is feasible for eliminating prolapsed pedunculated submucous myoma. It is simple and safe and can be performed in the outpatient setting.

Pacemaker implantation for persistent sinus node dysfunction in a patient with COVID-19.

A 46-year-old woman was admitted with coronavirus disease-2019 infection. Symptomatic sinus bradycardia occurred, followed by congestive heart failure. Therapeutics such as isoproterenol, theophylline, and cilostazol could not safely improve her symptoms. She underwent pacemaker implantation 53 days after admission. Atrial pacing remained was at 60% after 6 months.

New Series of Zaxinone Mimics (MiZax) for Fundamental and Applied Research.

The apocarotenoid zaxinone is a recently discovered regulatory metabolite required for proper rice growth and development. In addition, zaxinone and its two mimics (MiZax3 and MiZax5) were shown to have a remarkable growth-promoting activity on crops and a capability to reduce infestation by the root parasitic plant Striga through decreasing strigolactone (SL) production, suggesting their potential for application in agriculture and horticulture. In the present study, we developed a new series of MiZax via structural modification of the two potent zaxinone mimics (MiZax3 and MiZax5) and evaluated their effect on plant growth and Striga infestation. In general, the structural modifications to MiZax3 and MiZax5 did not additionally improve their overall performance but caused an increase in certain activities. In conclusion, MiZax5 and especially MiZax3 remain the likely most efficient zaxinone mimics for controlling Striga infestation.

Zaxinone mimics (MiZax) efficiently promote growth and production of potato and strawberry plants under desert climate conditions.

Climate changes and the rapid expanding human population have become critical concerns for global food security. One of the promising solutions is the employment of plant growth regulators (PGRs) for increasing crop yield and overcoming adverse growth conditions, such as desert climate. Recently, the apocarotenoid zaxinone and its two mimics (MiZax3 and MiZax5) have shown a promising growth-promoting activity in cereals and vegetable crops under greenhouse and field conditions. Herein, we further investigated the effect of MiZax3 and MiZax5, at different concentrations (5 and 10 µM in 2021; 2.5 and 5 µM in 2022), on the growth and yield of the two valuable vegetable crops, potato and strawberry, in the Kingdom of Saudi of Arabia. Application of both MiZax significantly increased plant agronomic traits, yield components and total yield, in five independent field trials from 2021 to 2022. Remarkably, the amount of applied MiZax was far less than humic acid, a widely applied commercial compound used here for comparison. Hence, our results indicate that MiZax are very promising PGRs that can be applied to promote the growth and yield of vegetable crops even under desert conditions and at relatively low concentrations.

Unusual trocar site metastasis in a uterine leiomyosarcoma after laparoscopic hysterectomy.

With widespread use of laparoscopy in patients with gynecologic malignancy, occasionally port-site metastasis is an item of concern. Herein we report a case of leiomyosarcoma of the uterus that metastasized to an accessory port after laparoscopic-assisted vaginal hysterectomy. A 46-year-old woman with a preoperative diagnosis of leiomyoma underwent laparoscopic-assisted vaginal hysterectomy. Final histopathologic findings revealed leiomyosarcoma. A postoperative abdominopelvic computed tomography scan demonstrated no evidence of metastatic tumor. The patient received 6 courses of combined chemotherapy consisting of cisplatin and ifosfamide. Follow-up computed tomography was performed because of pelvic pain at 4 months after treatment and revealed a recurrent pelvic tumor and a metastatic mass at previous right trocar site. At debulking surgery, a pelvic mass measuring 10 cm was observed, and a subcutaneous nodule measuring 4 cm was noted at the site of the right accessory port, with intact underlying peritoneum. After complete removal of both tumors, concurrent chemoradiation consisting of external radiotherapy and cisplatin was administered. Six months after the second surgery, a pelvic mass measuring 15 cm was observed. A second debulking surgical procedure was performed. However, the patient died of the disease 6 months after the second recurrence.

Striga hermonthica Suicidal Germination Activity of Potent Strigolactone Analogs: Evaluation from Laboratory Bioassays to Field Trials.

The obligate hemiparasite Striga hermonthica is one of the major global biotic threats to agriculture in sub-Saharan Africa, causing severe yield losses of cereals. The germination of Striga seeds relies on host-released signaling molecules, mainly strigolactones (SLs). This dependency opens up the possibility of deploying SL analogs as "suicidal germination agents" to reduce the accumulated seed bank of Striga in infested soils. Although several synthetic SL analogs have been developed for this purpose, the utility of these compounds in realizing the suicidal germination strategy for combating Striga is still largely unknown. Here, we evaluated the efficacy of three potent SL analogs (MP3, MP16, and Nijmegen-1) under laboratory, greenhouse, and farmer's field conditions. All investigated analogs showed around a 50% Striga germination rate, equivalent to a 50% reduction in infestation, which was comparable to the standard SL analog GR24. Importantly, MP16 had the maximum reduction of Striga emergence (97%) in the greenhouse experiment, while Nijmegen-1 appeared to be a promising candidate under field conditions, with a 43% and 60% reduction of Striga emergence in pearl millet and sorghum fields, respectively. These findings confirm that the selected SL analogs appear to make promising candidates as simple suicidal agents both under laboratory and real African field conditions, which may support us to improve suicidal germination technology to deplete the Striga seed bank in African agriculture.

Evaluation of the Biostimulant Activity of Zaxinone Mimics (MiZax) in Crop Plants.

Global food security is a critical concern that needs practical solutions to feed the expanding human population. A promising approach is the employment of biostimulants to increase crop production. Biostimulants include compounds that boost plant growth. Recently, mimics of zaxinone (MiZax) were shown to have a promising growth-promoting effect in rice (Oryza sativa). In this study, we investigated the effect of MiZax on the growth and yield of three dicot horticultural plants, namely, tomato (Solanum lycopersicum), capsicum (Capsicum annuum), and squash (Cucurbita pepo) in different growth environments, as well as on the growth and development of the monocot date palm (Phoenix dactylifera), an important crop in the Middle East. The application of MiZax significantly enhanced plant height, flower, and branch numbers, fruit size, and total fruit yield in independent field trials from 2020 to 2021. Importantly, the amount of applied MiZax was far less than that used with the commercial compound humic acid, a widely used biostimulant in horticulture. Our results indicate that MiZax have significant application potential to improve the performance and productivity of horticultural crops.

Radiosensitization using hydrogen peroxide in patients with cervical cancer.

The purpose of the present study was to analyze the feasibility and safety of radiosensitization using hydrogen peroxide for cervical cancer. In superficial tumors, breast cancer and hepatocellular carcinoma, the safety and effectiveness of radiosensitization has been reported; to the best of our knowledge, however, there are no reports on cervical cancer. A total of 20 patients with cervical cancer were recruited. Inclusion criteria were as follows: Patients who required radical external beam radiotherapy (RT); ineligible for or refused brachytherapy; age, ≥20 years; no hematogenous metastasis; Eastern Cooperative Oncology Group Performance Status up to 2; and had not undergone prior treatment. Hydrogen peroxide was used twice a week in combination with RT. A 3% hydrogen peroxide solution-soaked gauze was inserted into the vagina during RT. A total of 45 Gy was delivered in 25 fractions to the whole pelvis with a boost of 10 Gy in 5 fractions if pelvic or para-aortic metastatic lymph nodes were observed. Ultimately, 18 patients were evaluated. Among the 17 patients (excluding one patient with tumor in situ), the one- and two-year overall survival rates were both 90% in patients with stage I/II and 86% in stage III/IV cervical cancer. The adverse events were well tolerated with no severe acute or late adverse events. Although limited by small sample size, short observation time and low radiation dose, the present study demonstrated that radiosensitization treatment may be an option for patients who cannot undergo brachytherapy. The study was retrospectively registered at the university hospital medical information network center (no. UMIN000039045) on January 6, 2020.

Neoadjuvant chemotherapy followed by radical hysterectomy plus postoperative chemotherapy but no radiotherapy for Stage IB2-IIB cervical cancer--irinotecan and platinum chemotherapy.

OBJECTIVE: To evaluate the effectiveness of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy plus postoperative chemotherapy but no radiotherapy for stage IB2-IIB cervical cancer. METHODS: Forty-six consecutive patients with stage IB2-IIB cervical cancer were treated with NAC followed by radical hysterectomy plus postoperative chemotherapy. Median (range) body mass index (BMI) of the patients was 20.2 (16.2-26.4). Regimens for NAC and postoperative chemotherapy were irinotecan and cisplatin (CPT-11/CDDP) or CPT-11 and nedaplatin (CPT-11/NDP). A total of six cycles of NAC and postoperative chemotherapy were prescribed. No use of radiotherapy was scheduled, except in the case of a recurrence. RESULTS: With a median follow-up period for survivors of 38.8 months (range 24-54 months), the 2- and 3-year progression-free survival rates were 91.2% and 86.1%, respectively. Overall response rate of NAC was 80.4%. Recurrence was observed in seven patients. In the absence of radiotherapy, pelvic recurrence was observed in only three patients; another two had para-aortic lymph nodes and the remaining two distant metastases. Toxicities due to chemotherapy were generally tolerable. Postoperative complications included urinary fistula (four patients, 8.7%) and bowel obstruction (two patients, 4.3%), all of which required surgical intervention. CONCLUSION: The results indicate that NAC followed by surgery plus postoperative chemotherapy but no radiotherapy offers a viable option in the treatment of stage IB2-IIB cervical cancer. Although a relatively large incidence of postsurgical complications was observed among low-BMI patients, this treatment offers the advantage of minimizing radiation-induced morbidity, allowing radiotherapy to be reserved for the possible event of pelvic recurrence.

Shimodaira-Taniguchi conization method: its utility and reliability.

INTRODUCTION: Introduced in 1992, the Shimodaira-Taniguchi conization procedure addresses the disadvantages of the loop electrosurgical excision procedure by relying on a high frequency current of 150 W and a triangular probe with a 0.25-mm linear excision electrode to extract a single informative specimen. We conducted a retrospective study to evaluate Shimodaira-Taniguchi conization as a conservative therapy for cervical intraepithelial neoplasia (CIN) and microinvasive cancer of the cervix. METHODS: Subjects were 455 patients who underwent Shimodaira-Taniguchi conization for CIN, carcinoma in situ, adenocarcinoma in situ, or stage IA microinvasive cervical carcinoma at our hospital from January 2005 to December 2008. Patient follow-up ranged from 13 to 60 months. Clinical data were obtained and evaluated. RESULTS: Mean operation time was 11 minutes, and average blood loss was 9.9 mL. Margins were positive in 178 (39.1%) cases. Postsurgical complications occurred in 61 patients, with secondary hemorrhage occurring in 46 patients. None required transfusion. None were lost to follow-up, and there was no disease-related death. Disease recurred in 6 (1.3%) patients: 4 with a positive excision margin and 2 with a negative margin. Cervical stenosis occurred in 15 (3.3%) patients, 3 of whom suffered cervical obstruction, including 1 with dysmenorrhea who underwent hysterectomy. In most cases (n = 357, 78%), a single adequate specimen was extracted. CONCLUSIONS: As a conservative treatment for CIN and microinvasive cervical cancer, Shimodaira-Taniguchi conization is useful. It is easy, provides adequate histologic specimens (often singular), and results in few postoperative complications.

Abdominal Myomectomy for Huge Uterine Myomas with Intra-arterial Balloon Occlusion: Approach to Reduce Blood Loss.

Abdominal myomectomy for a huge myomas, especially uterine cervical myoma, is difficult because of risks, such as intraoperative bleeding or injury to adjacent organs. Therefore, understanding of the positional relationships among a huge myoma, especially cervical or intraligamental myoma, and the vascular plexuses in the right and left cardinal ligaments is important for prevention of massive bleeding during myomectomy. While sufficiently performing preoperative assessment with pelvic examination, ultrasonography, magnetic resonance imaging (MRI), etc., surgeons should always keep in mind how they can reduce the blood loss volume, while safely and surely performing resections. For a cervical myoma of the uterus and giant uterine leiomyoma that leave no intrapelvic space and prevent palpation and identification of the uterine arteries and the internal iliac arteries, surgery can be performed safely by preoperatively placing balloon catheters in the internal iliac arteries. Hemostaic strategies for myomectomy and tips of subsequent pregnancy following myomectomy are also described.

A New Series of Carlactonoic Acid Based Strigolactone Analogs for Fundamental and Applied Research.

Strigolactones (SLs) are a group of carotenoid derived plant hormones that play a key role in establishing plant architecture and adapting it to environmental changes, and are involved in plants response to biotic and abiotic stress. SLs are also released into the soil to serve as a chemical signal attracting beneficial mycorrhizal fungi. However, this signal also induces seed germination in root parasitic weeds that represent a major global threat for agriculture. This wide spectrum of biological functions has made SL research one of the most important current topics in fundamental and applied plant science. The availability of SLs is crucial for investigating SL biology as well as for agricultural application. However, natural SLs are produced in very low amounts, and their organic synthesis is quite difficult, which creates a need for efficient and easy-to-synthesize analogs and mimics. Recently, we have generated a set of SL analogs, Methyl Phenlactonoates (MPs), which resemble the non-canonical SL carlactonoic acid. In this paper, we describe the development and characterization of a new series of easy-to-synthesize MPs. The new analogs were assessed with respect to regulation of shoot branching, impact on leaf senescence, and induction of seed germination in different root parasitic plants species. Some of the new analogs showed higher efficiency in inhibiting shoot branching as well as in triggering parasitic seed germination, compared to the commonly used GR24. MP16 was the most outstanding analog showing high activity in different SL biological functions. In summary, our new analogs series contains very promising candidates for different applications, which include the usage in studies for understanding different aspects of SL biology as well as large scale field application for combating root parasitic weeds, such as Striga hermonthica that devastates cereal yields in sub-Saharan Africa.