Correction: 2-cyanopyridine derivatives enable N-terminal cysteine bioconjugation and peptide bond cleavage of glutathione under aqueous and mild conditions.

[This corrects the article DOI: 10.1039/D4RA00437J.].

Tuberculous peritonitis diagnosed following laparoscopic examination for suspected advanced ovarian cancer.

Laparoscopy for intra-abdominal exploration and tissue sampling is useful in advanced ovarian cancers, in which it is presumed to be difficult to achieve complete tumour reduction in the initial surgery. This is a report of a case of suspected advanced ovarian cancer in a patient, who underwent laparoscopic screening and was later pathologically diagnosed with tuberculous peritonitis. A woman in her 50s visited her local doctor with constipation. Since imaging showed massive ascites she was referred for further evaluation. We initially suspected advanced ovarian cancer due to the presence of massive ascites and multiple peritoneal nodules. However, histopathological examination indicated that the nodules were tubercles, and the patient was subsequently diagnosed with tuberculous peritonitis. It is important to be aware that tuberculosis peritonitis can be misdiagnosed or mistaken for advanced ovarian cancer. Preoperative diagnosis of tuberculous peritonitis is often difficult. Tuberculous peritonitis should be considered if intraoperative findings show diffuse nodular disseminated lesions.

Comparison of Urinary Liver Fatty Acid Binding Protein Level and Pathologic Biopsy Findings 1 Year After Kidney Transplantation.

BACKGROUND: For the early detection of abnormal findings considering for therapeutic intervention, we regularly undertake protocol renal allograft biopsy at 1 year after kidney transplantation (KT). We examined whether urinary liver fatty acid binding protein (L-FABP) level predicts some pathologic findings of renal allograft. METHODS: We retrospectively enrolled recipients with stable graft function who routinely were biopsied renal allograft specimens 1 year after KT between January 2015 and May 2021 in our center. We assessed the association urinary L-FABP level with pathologic findings of renal allograft biopsies. RESULTS: We enrolled 56 recipients in this study. Their median age at KT was 49.5 and their median serum creatinine at 1 year after KT was 1.22 mg/dL. In 9 of 56 patients, abnormal high value of urinary L-FABP were observed. All of them had abnormal findings pathologically in the renal allografts (border line change 3, medullary ray injury [MRI] with calcineurin inhibitor toxicity [CNI-T] 1, MRI without CNI-T 1, CNI-T with IgA deposition 1, and BK virus nephropathy 3). On the other hand, 30 of 47 patients with normal value of urinary LFABP had no pathologically abnormal findings. Both specificity and positive predictive value of urinary L-FABP for pathologic findings were 100.0༅. CONCLUSIONS: Our results suggest that patients with renal transplant with elevated urinary L-FABP levels might benefit from renal allograft biopsy. Comparison of urinary liver fatty acid binding protein level and pathologic biopsy findings 1 year after KT.

Oligoarginine-Conjugated Peptide Foldamers Inhibiting Vitamin D Receptor-Mediated Transcription.

The vitamin D receptor (VDR) is a nuclear receptor, which is involved in several physiological processes, including differentiation and bone homeostasis. The VDR is a promising target for the development of drugs against cancer and bone-related diseases. To date, several VDR antagonists, which bind to the ligand binding domain of the VDR and compete with the endogenous agonist 1α,25(OH)D3, have been reported. However, these ligands contain a secosteroidal skeleton, which is chemically unstable and complicated to synthesize. A few VDR antagonists with a nonsecosteroidal skeleton have been reported. Alternative inhibitors against VDR transactivation that act via different mechanisms are desirable. Here, we developed peptide-based VDR inhibitors capable of disrupting the VDR-coactivator interaction. It was reported that helical SRC2-3 peptides strongly bound to the VDR and competed with the coactivator in vitro. Therefore, we designed and synthesized a series of SRC2-3 derivatives by the introduction of nonproteinogenic amino acids, such as ß-amino acids, and by side-chain stapling to stabilize helical structures and provide resistance against digestive enzymes. In addition, conjugation with a cell-penetrating peptide increased the cell membrane permeability and was a promising strategy for intracellular VDR inhibition. The nona-arginine-conjugated peptides 24 with side-chain stapling and 25 with cyclic ß-amino acids showed strong intracellular VDR inhibitory activity, resulting in suppression of the target gene expression and inhibition of the cell differentiation of HL-60 cells. Herein, the peptide design, structure-activity relationship (SAR) study, and biological evaluation of the peptides are described.

Bilateral Encrusted Metallic Stent Successfully Removed by Ureteroscopic Lithotripsy Using a Ho:YAG Laser in a Patient with Malignant Myeloma.

Ureteral stent encrustation is sometimes encountered, especially in cases in which a ureteral stent has been forgotten. An 84-year-old female patient with malignant myeloma underwent metallic ureteral stent insertion to treat malignant ureteral obstruction. At the time of scheduled ureteral stent exchange, the stent was heavily encrusted and could not be removed on either side. We performed endoscopic lithotripsy to remove the encrusted ureteral stents. The bilaterally encrusted metallic ureteral stents were successfully removed using Ho:YAG laser lithotripsy after inserting another ureteral stent placement besides the encrusted metallic ureteral stents.

Sarcomatoid Variant of Bladder Carcinoma: A Case Report.

A 59-year-old man was referred to our hospital complaining of asymptomatic gross hematuria. Cystoscopy revealed a papillary tumor 8 cm in diameter filling the bladder. The patient underwent transurethral resection of the bladder tumor. The pathological findings revealed the sarcomatoid variant of urothelial carcinoma with a heterologous osteosarcomatous element. He had no metastasis according to our imaging analyses; thus, we planned radical cystectomy after two courses of neoadjuvant chemotherapy (gemcitabine and cisplatin). Following chemotherapy, enlarged pelvic lymph nodes were noted, and extremely aggressive local progression of the bladder tumor was confirmed. The patient ultimately died 6 months after his initial visit to our hospital.

Neutrophil-to-Lymphocyte Ratio in Renal Transplant Patients.

OBJECTIVES: Because of recent developments in immunosuppressive therapy, renal transplant outcomes have improved. Although reports on the association between immunosuppressive therapy and malignant disease are available, the results are controversial. The neutrophil-to-lymphocyte ratio has been reported as an easy tumor marker for predicting the prognoses of some solid tumors. In the present study, we examined changes in neutrophil-to-lymphocyte ratio after renal transplant and discussed cases in which malignant disease developed after renal transplant. MATERIALS AND METHODS: Our study included 137 patients who underwent renal transplant between August 2001 and September 2015. Four of these patients (2.9%) developed malignant disease. The neutrophil-to-lymphocyte ratio was calculated based on the numbers of neutrophils and lymphocytes in the complete blood count and evaluated before and at 1, 3, 6, and 12 months and at 3 years after renal transplant. RESULTS: The neutrophil-to-lymphocyte ratio was markedly high at 1 week and 1 month after renal transplant and gradually decreased until it became stable at 3 months posttransplant. In patients with malignant disease, there was a gradual increase in the neutrophil-to-Iymphocyte ratio after renal transplant. CONCLUSIONS: We observed dramatic differences in the neutrophil-to-lymphocyte ratio at 1 and 3 months after renal transplant. The neutrophil-to-lymphocyte ratio of patients with malignant disease after renal transplant continued to increase.

Laminar flow downregulates Notch activity to promote lymphatic sprouting.

The major function of the lymphatic system is to drain interstitial fluid from tissue. Functional drainage causes increased fluid flow that triggers lymphatic expansion, which is conceptually similar to hypoxia-triggered angiogenesis. Here, we have identified a mechanotransduction pathway that translates laminar flow-induced shear stress to activation of lymphatic sprouting. While low-rate laminar flow commonly induces the classic shear stress responses in blood endothelial cells and lymphatic endothelial cells (LECs), only LECs display reduced Notch activity and increased sprouting capacity. In response to flow, the plasma membrane calcium channel ORAI1 mediates calcium influx in LECs and activates calmodulin to facilitate a physical interaction between Krüppel-like factor 2 (KLF2), the major regulator of shear responses, and PROX1, the master regulator of lymphatic development. The PROX1/KLF2 complex upregulates the expression of DTX1 and DTX3L. DTX1 and DTX3L, functioning as a heterodimeric Notch E3 ligase, concertedly downregulate NOTCH1 activity and enhance lymphatic sprouting. Notably, overexpression of the calcium reporter GCaMP3 unexpectedly inhibited lymphatic sprouting, presumably by disturbing calcium signaling. Endothelial-specific knockouts of Orai1 and Klf2 also markedly impaired lymphatic sprouting. Moreover, Dtx3l loss of function led to defective lymphatic sprouting, while Dtx3l gain of function rescued impaired sprouting in Orai1 KO embryos. Together, the data reveal a molecular mechanism underlying laminar flow-induced lymphatic sprouting.

[Pulmonary Mycobacterium Avium-Complex (MAC) Disease Differentially Diagnosed from Metastasis of Testicular Cancer : A Case Report].

A 45 year-old-man was admitted to our hospital because of discomfort in his left scrotum. He had a left testicular tumor. We performed high orchiectomy and pathological findings revealed testicular cancer. He was treated with bleomycin, etoposide and cisplatin. Computed tomography showed a new mass in the left lung after 3 cycles of the chemotherapy. Because of its rapid growth, the tumor was thought to be a metastasis lesion of testicular cancer or pulmonary infection. Transbronchial lung biopsy showed an invasion of multinucleated giant cells and granuloma. The culture and polymerase chain reaction of the bronchial sputum were positive for myobacterium avium-complex (MAC). From these findings, the left lung tumor was diagnosed as pulmonary MAC disease. He received partial resection of the left lung and the lesion was diagnosed as granuloma. There was no recurrence of testicular cancer or pulmonary disease after the surgery.

Binding of smoothelin-like 1 to tropomyosin and calmodulin is mutually exclusive and regulated by phosphorylation.

BACKGROUND: The smoothelin-like 1 protein (SMTNL1) can associate with tropomyosin (Tpm) and calmodulin (CaM), two proteins essential to the smooth muscle contractile process. SMTNL1 is phosphorylated at Ser301 by protein kinase A during calcium desensitization in smooth muscle, yet the effect of SMTNL1 phosphorylation on Tpm- and CaM-binding has yet to be investigated. RESULTS: Using pull down studies with Tpm-Sepharose and CaM-Sepharose, we examined the interplay between Tpm binding, CaM binding, phosphorylation of SMTNL1 and calcium concentration. Phosphorylation greatly enhanced the ability of SMTNL1 to associate with Tpm in vitro; surface plasmon resonance yielded a 10-fold enhancement in K D value with phosphorylation. The effect on CaM binding is more complex and varies with the availability of calcium. CONCLUSIONS: Combining both CaM and Tpm with SMTNL1 shows that the binding to both is mutually exclusive.

The Calcium-Dependent Switch Helix of L-Plastin Regulates Actin Bundling.

L-plastin is a calcium-regulated actin-bundling protein that is expressed in cells of hematopoietic origin and in most metastatic cancer cells. These cell types are mobile and require the constant remodeling of their actin cytoskeleton, where L-plastin bundles filamentous actin. The calcium-dependent regulation of the actin-bundling activity of L-plastin is not well understood. We have used NMR spectroscopy to determine the solution structure of the EF-hand calcium-sensor headpiece domain. Unexpectedly, this domain does not bind directly to the four CH-domains of L-plastin. A novel switch helix is present immediately after the calcium-binding region and it binds tightly to the EF-hand motifs in the presence of calcium. We demonstrate that this switch helix plays a major role during actin-bundling. Moreover a peptide that competitively inhibits the association between the EF-hand motifs and the switch helix was shown to deregulate the actin-bundling activity of L-plastin. Overall, these findings may help to develop new drugs that target the L-plastin headpiece and interfere in the metastatic activity of cancer cells.

Overexpression of Antimicrobial, Anticancer, and Transmembrane Peptides in Escherichia coli through a Calmodulin-Peptide Fusion System.

In recent years, the increasing number of antibiotic-resistant bacteria has become a serious health concern. Antimicrobial peptides (AMPs) are an important component of the innate immune system of most organisms. A better understanding of their structures and mechanisms of action would lead to the design of more potent and safer AMPs as alternatives for current antibiotics. For detailed investigations, effective recombinant production which allows the facile modification of the amino acid sequence, the introduction of unnatural amino acids, and labeling with stable isotopes for nuclear magnetic resonance (NMR) studies is desired. Several expression strategies have been introduced in previous reports; however, their effectiveness has been limited to a select few AMPs. Here, we have studied calmodulin (CaM) as a more universal carrier protein to express many types of AMPs in E. coli. We have discovered that the unique architecture of CaM, consisting of two independent target binding domains with malleable methionine-rich interaction surfaces, can accommodate numerous amino acid sequences containing basic and hydrophobic residues. This effectively masks the toxic antimicrobial activities of many amphipathic AMPs and protects them from degradation during expression and purification. Here, we demonstrate the expression of various AMPs using a CaM-fusion expression system, including melittin, fowlicidin-1, tritrpticin, indolicidin, puroindoline A peptide, magainin II F5W, lactoferrampin B, MIP3α51-70, and human ß-defensin 3 (HBD-3), the latter requiring three disulfide bonds for proper folding. In addition, our approach was extended to the transmembrane domain of the cell adhesion protein l-selectin. We propose the use of the CaM-fusion system as a universal approach to express many cationic amphipathic peptides that are normally toxic and would kill the bacterial host cells.

[The Diagnostic Value of Pre-Biopsy Magnetic Resonance Imaging (MRI) for Detecting Prostate Cancer].

We examined the value of pre-biopsy magnetic resonance imaging (MRI) for detecting prostate cancer. We analyzed 267 men with prostate-specific antigen (PSA) levels of 3-10 ng/ml who underwent systematic prostate needle biopsy. From April 2009 to March 2011, a total of 98 male patients underwent 16-core prostatic biopsies without pre-biopsy magnetic resonance imaging (MRI) (nonenforcement group). From April 2011 to March 2013, 169 men underwent pre-biopsy MRI [T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI)] (enforcement group). When MRI findings indicated cancer in the latter group, in addition to the systematic 16-core biopsy one or two targeted biopsies were performed. Patients without suspicious MRI findings underwent only systematic 16-core biopsy. Cancer detection rates in the nonenforcement and enforcement groups were 42.9% (48/92) and 46. 2% (78/169), respectively. The difference did not reach significance (p＝0.612). Although the cancer detection rates were 39.4% (41/104) in the MRI-negative group and 56. 9% (37/65) in the MRI-positive group (p＝0.039), the sensitivity and specificity for cancer detection by MRI were relatively low: 47.4% and 69.2%, respectively. By receiver-operating curve analysis, the area under the curve for cancer detection by MRI was only 0.583. There were two study limitations. First, the patient sample size was small. Second, it is unclear whether an adequate sample of the suspicious lesion was obtained by biopsy. We thus demonstrated that it might be improper to base a diagnosis solely on pre-biopsy MRI (T2WI and DWI) findings in men with serum PSA levels of 3-10 ng/ml.

Invasive urothelial carcinoma, lymphoma-like/plasmacytoid variant, successfully treated by radical cystectomy with adjuvant chemotherapy: a case report.

BACKGROUND: Invasive urothelial carcinoma, lymphoma-like/plasmacytoid variant, is a rare histological type of bladder cancer similar to plasma cells and is an aggressive variant of urothelial carcinoma associated with a poor prognosis. CASE PRESENTATION: A 41-year-old Asian man was referred to our hospital due to macroscopic hematuria. Cystoscopy detected a non-papillary tumor, and a transurethral resection of the bladder tumor revealed pT1N0M0 bladder cancer. A pathological examination showed high-grade invasive urothelial carcinoma and a component of signet ring cell carcinoma. A follow-up of the transurethral resection with radical cystectomy was carried out, and a pathological examination showed infiltrating urothelial carcinoma, with partial features of the plasmacytoid variant. We added chemotherapy treatment with gemcitabine and cisplatin for two cycles. Our patient has been free from recurrence for 2 years. CONCLUSIONS: We herein report the case of a patient with a plasmacytoid variant of urothelial carcinoma controlled with radial cystectomy and subsequent chemotherapy.

PHEOCHROMOCYTOMA DURING PREGNANCY-2 CASE REPORTS.

(Introduction) A pheochromocytoma diagnosed during pregnancy is rare, and also its fetal and maternal mortality is high if undiagnosed. We report two cases with successful pregnancy outcome with pheochromocytoma. (Case 1) A 31-years-old previously healthy woman presented at 19 week period of gestation with high blood pressure. High urine catecholamine level and a left adrenal mass recognized by magnetic resonance imaging (MRI) confirmed adrenal pheochromocytoma. The patient had good blood pressure control after we started doxazosin 4 mg daily, and Caesarean section was performed at 35 week period of gestation. Two months after delivery, laparoscopic adrenalectomy was performed and she was discharged in the absence of hypertension. (Case 2) A 31-years-old previously healthy woman presented at 29 week period of gestation with exacerbation of headache and palpitation. High urine catecholamine level and a mass recognized close to the inferior vena cava by MRI confirmed extraadrenal pheochromocytoma. The patient had good blood pressure after we started doxazosin 4 mg daily and labetalol hydrochloride 200 mg daily. Caesarean section was performed at 35 week period of gestation. One month after delivery, laparotomic resection of the tumor was performed. Seven years later, hypertension reoccurred and there was an extraadrenal pheochromocytoma recurrence. We had a laparotomic resection for the recurrent tumor, and now she is in the absence of hypertension. (Conclusion) Pheochromocytoma should be considered as a differential diagnosis in a case of high blood pressure occurred during pregnancy. Early detection and appropriate treatment is crucial to reduce fetal and maternal mortality.

Highly improved accuracy of the revised PREoperative sarcoma score (rPRESS) in the decision of performing surgery for patients presenting with a uterine mass.

In 2014, we published an article titled "Novel uterine sarcoma preoperative diagnosis score predicts the need for surgery in patients presenting with a uterine mass" on the preoperative diagnosis of uterine sarcoma, in the SpringerPlus (Nagai et al. in SpringerPlus 2014, 3:678. doi:10.1186/2193-1801-3-678). Subsequently, we received several suggestions from readers, which were used to modify the statistical analysis methods and create a more precise preoperative diagnostic scoring system, which we present here as a supplemental report. The subjects were 63 patients who underwent surgical therapy for suspected uterine sarcoma (sarcoma group: 15 patients, benign group: 48 patients). Logistic regression analysis using the exact method was performed considering the subjects' preoperative age, serum lactate dehydrogenase levels, magnetic resonance imaging findings, and endometrial cytology findings. We then used parameter estimates obtained from this analysis to revise the PREoperative Sarcoma Score (PRESS). The revised PRESS (rPRESS) has a maximum score of 10 points and an optimal cut-off value of 4 points, as derived from a receiver operating characteristic curve. Using this, the accuracy, positive predictive value, and negative predictive value were 93.7, 92.3, and 94.0 %, respectively. The diagnostic precision of the rPRESS is better than that of the original PRESS.

Primary retroperitoneal mucinous cystic tumors with borderline malignancy: a case report and literature review.

Primary retroperitoneal mucinous cystic tumors with borderline malignancy are rarely encountered. To date, only 12 cases have been reported in the literature. In this report, we present an additional case. A 65-year-old nulliparous woman complained of abdominal fullness. Her medical history included a hysterectomy and a single salpingo-oophorectomy performed 25 years prior to the present event. Physical examination revealed a large cystic mass in the abdomen and pelvis. During laparotomy, a cystic tumor measuring 21×14 cm in size was observed in the left retroperitoneal space. The tumor was resected, and the final diagnosis was primary retroperitoneal mucinous cystic cancer with borderline malignancy.

Concomitant sentinel lymph node biopsy leading to abbreviated systematic lymphadenectomy in a patient with primary malignant melanoma of the vagina.

INTRODUCTION: Primary malignant melanoma of the vagina is an extremely rare disease affecting 3% of patients with malignant vaginal tumors. It is rare compared to primary malignant melanoma of the skin and its prognosis is unfavorable even in patients with Stage I disease. Here, we report a case of primary malignant melanoma of the vagina and discuss our experience with regard to previously published literature. CASE DESCRIPTION: The patient was a 59-year-old female with 2 prior pregnancies and child births. She was examined by a local doctor for swelling of the genitalia, and a 1.8 × 1.0 cm large tumor was detected on the left side of the vaginal wall. A biopsy indicated leiomyosarcoma, and she was referred to our hospital. The tumor was resected, and histopathology of the resected sample confirmed the diagnosis of malignant melanoma based on a positive surgical margin. Additional courses of treatment included left inguinal sentinel lymph node biopsy using an isotope and extended vaginectomy. Although the sentinel node was negative, we performed a modified radical hysterectomy and left vaginectomy during the third operation because the surgical margin was positive. We could not confirm whether the lesion in the extracted sample was malignant, and the final diagnosis was primary malignant melanoma of the vagina T4bN0M0 Stage IIc (UICC 2009). Postoperative adjuvant therapy consisted of 6 cycles of DAV-Feron therapy (dacarbazine, ACNU, vincristine, IFN- ß). After 5 months of postoperative adjuvant therapy, a 2 cm single lung metastasis was detected in the lower left lung. We performed a laparoscopic lower left lobectomy and are planning additional chemotherapy. DISCUSSION AND EVALUATION: Currently, surgical resection has the highest probability of improving the prognosis of patients when used as initial treatment for Stage I disease. By combining treatment with sentinel lymph node biopsy, we were able to accurately determine the stage of disease and thus avoid systematic lymph node dissection and further surgical treatments. CONCLUSION: Malignant melanoma of the vagina is very rare tumor so it is necessary to requires the integration of further cases.

Novel uterine sarcoma preoperative diagnosis score predicts the need for surgery in patients presenting with a uterine mass.

Preoperative diagnosis of uterine sarcoma is very difficult, and currently, its diagnostic accuracy is not satisfactory. It is therefore important to perform surgery and establish the pathological diagnosis if the clinical findings and various examination findings indicate possible uterine sarcoma. We investigated the accuracy of the combination of various types of predictors of uterine sarcoma and the novel PREoperative Sarcoma Score (PRESS) for avoiding unnecessary surgery while diagnosing uterine sarcoma. We retrospectively analyzed the clinical findings, blood tests, imaging studies (ultrasonography and magnetic resonance imaging [MRI]), and endometrial cytology of 63 suspected uterine sarcoma cases that underwent surgery from 2006 to 2012. These cases were also scored retrospectively using PRESS. We analyzed the number of unnecessary surgeries that could be avoided using PRESS. Of 63 cases, 15 were diagnosed with uterine sarcoma (sarcoma group), and 48 had benign tumors (benign group). Univariate analysis indicated age, serum lactate dehydrogenase (LDH) values, and MRI and endometrial cytology findings as significant predictors of uterine sarcoma in both groups. In contrast, multivariable analysis identified only age, serum LDH value, and endometrial cytology findings as significant predictors. Accordingly, the latter were placed as 2 points, and the remaining MRI finding as 1 point. The accuracy rate of prediction was 84.1%, and the positive and negative predictive values were 63.2% and 93.2% respectively when the PRESS was interpreted as "positive" when it was 3 points or higher. Using multiple predictors for the preoperative diagnosis of uterine sarcoma, our proposed PRESS score is beneficial in the clinical setting while making treatment decisions in suspected uterine sarcoma cases as well as avoiding unnecessary surgery.

[Neoadjuvant and adjuvant chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for advanced penile cancer: a case report].

54-year-old male was introduced to our hospital in January 2012 for surgical treatment and chemotherapy. The pathological examination revealed well differentiated squamous cell carcinoma of the penis. Computed tomography and magnetic resonance imaging indicated right inguinal and pelvic lymphadenopathy. We diagnosed the tumor to be unresectable radically and administered paclitaxel, cisplatin and 5-fluorouracil (TPF) as neoadjuvant chemotherapy. After 3 courses of chemotherapy, the size of lymphadenopathy had become small enough to allow curative surgical treatment. Partial penectomy and lymph node dissection were performed after neoadjuvant chemotherapy. For 12 months after this radical treatment, the patient has been healthy with no local resurrence and no distant metastatic lesion. TPF chemotherapy for unresectable nodal metastasis from squamous cell carcinoma of penis was suggested to be effective.