Breast fat necrosis secondary to warfarin-induced calciphylaxis,a rare mimicker of breast cancer: A case report and a review of literature

Breast fat necrosis (BFN) is usually a benign inflammatory response to breast trauma. However, an extremely rare cause of fat necrosis is calciphylaxis, a calcification of small- and medium-sized arteries causing thrombosis and ischemia. It is classified into (A) uremic (B) nonuremic-induced calciphylaxis. Calciphylaxis has been reported to be encountered in different parts of the body. However, to the best of our knowledge there is only one case in the English literature of BFN 2ry to warfarin-induced calciphylaxis. We report a 65-year-old female, known case of atrial fibrillation on warfarin, presented with a left breast mass of 4-month duration. The mass was painful and progressively enlarging. Examination of the left breast showed 7 × 4 cm mass, spanning from 10-2 o'clock, free from surrounding structures, with preserved overlying skin. However, the mass was not visualized on mammogram. Ultrasound showed a left breast lobulated hypoechoic mass containing a hyperechoic component. Biopsy showed fat necrosis. After 1 month, she presented with ulceration of the overlying skin. After wide local excision, histopathology demonstrated a calciphylaxis-induced fat necrosis. Considering the patient's background, the diagnosis was BFN secondary to warfarin-induced calciphylaxis. Hence, the warfarin was shifted to Rivaroxaban, 6 months follow-up showed no evidence of recurrence. In conclusion, the rarity of nonuremic calciphylaxis is reflected on the delay of diagnosis in some of the reported cases and the lack of grading system used to guide the management of such difficult wounds. However, keeping a high index of suspicion is important whenever such wounds are encountered with presence of risk factors other than end-stage kidney disease.     

Co-culture of the fungus Fusarium tricinctum with Streptomyces lividans induces production of cryptic naphthoquinone dimers

Co-cultivation of the endophytic fungus Fusarium tricinctum with Streptomyces lividans on solid rice medium led to the production of four new naphthoquinone dimers, fusatricinones A–D (1–4), and a new lateropyrone derivative, dihydrolateropyrone (5), that were not detected in axenic fungal controls. In addition, four known cryptic compounds, zearalenone (7), (−)-citreoisocoumarin (8), macrocarpon C (9) and 7-hydroxy-2-(2-hydroxypropyl)-5-methylchromone (10), that were likewise undetectable in extracts from fungal controls, were obtained from the co-culture extracts. The known antibiotically active compound lateropyrone (6), the depsipeptides enniatins B (11), B1 (12) and A1 (13), and the lipopeptide fusaristatin A (14), that were present in axenic fungal controls and in co-culture extracts, were upregulated in the latter. The structures of the new compounds were elucidated by 1D and 2D NMR spectra as well as by HRESIMS data. The relative and absolute configuration of dihydrolateropyrone (5) was elucidated by TDDFT-ECD calculations.

Naphthoquinone dimers from co-culture of Fusarium tricinctum with Streptomyces lividans.     

Honey-Based Extracts and Their Microemulsions in the Treatment of Liver and Breast Cancers

Pharmaceutical Chemistry Journal - Liquid-liquid fractionation was performed for two samples of honey, and the fractions were nanoencapsulated in microemulsions using the method of water dilution....     

A bimodular nuclear localization signal assembled via an extended double-stranded RNA-binding domain acts as an RNA-sensing signal for transportin 1

The human RNA-editing enzyme adenosine deaminase acting on RNA (ADAR1) carries a unique nuclear localization signal (NLS) that overlaps one of its double-stranded RNA-binding domains (dsRBDs). This dsRBD-NLS is recognized by the nuclear import receptor transportin 1 (Trn1; also called karyopherin-β2) in an RNA-sensitive manner. Most Trn1 cargos bear a well-characterized proline-tyrosine-NLS, which is missing from the dsRBD-NLS. Here, we report the structure of the dsRBD-NLS, which reveals an unusual dsRBD fold extended by an additional N-terminal α-helix that brings the N- and C-terminal flanking regions in close proximity. We demonstrate experimentally that the atypical ADAR1-NLS is bimodular and is formed by the combination of the two flexible fragments flanking the folded domain. The intervening dsRBD acts only as an RNA-sensing scaffold, allowing the two NLS modules to be properly positioned for interacting with Trn1. We also provide a structural model showing how Trn1 can recognize the dsRBD-NLS and how dsRNA binding can interfere with Trn1 binding.Trafficking of macromolecules between the nucleus and cytoplasm through nuclear pore complexes (NPCs) is a selective and efficient process orchestrated by transport receptors that associate with their cargoes via cognate nuclear localization signals (NLSs) or nuclear export signals (NESs). Transport receptors of the karyopherin-β (Kapβ) family, also known as importins and exportins, account for the vast majority of the cargo flow through the NPC. Transport directionality is primarily driven by the RanGTPase nucleotide cycle, which produces an asymmetric distribution of RanGTP and RanGDP on both sides of the nuclear envelope (1–4).Unlike importin-β, which forms a heterodimer with the adaptor importin-α to import substrates containing classical NLSs (cNLSs) (1, 5), transportin 1 (also known as Kapβ2; thereafter designated Trn1) binds cargoes in the cytoplasm without adaptors, targets them to the nucleus through the NPC, and releases them in the nucleus upon RanGTP binding (6, 7). In contrast to the well-defined cNLS recognized by importin-α, Trn1 recognizes a diverse set of sequences with poor apparent conservation that cannot be appropriately described by a conventional consensus sequence. Nevertheless, structural and biochemical studies uncovered a set of loose principles common to some Trn1 signals (8–11). These principles can be described as follows: a peptide segment of 15–30 residues with intrinsic structural disorder, an overall basic character, and some weakly conserved sequence motifs, including a relatively conserved proline-tyrosine (PY) dipeptide, leading to the name PY-NLS for this class of signals (8). However, many characterized Trn1 cargoes do not contain such a PY-NLS (4, 12–15). Therefore, Trn1 interacts not only with the well-characterized PY-NLSs, but at least with another class of NLS, the recognition of which is far less understood. Whether these other classes of NLS share some similarities with PY-NLSs remains to be determined.One Trn1 cargo that lacks a typical PY-NLS is the RNA-editing enzyme ADAR1, a member of the adenosine deaminases acting on RNA (ADARs) family. These enzymes convert adenosines to inosines by hydrolytic deamination in structured and double-stranded RNA substrates (16, 17). Inosines formed by adenosine deamination can alter the coding potential of mRNAs but also can affect splicing, localization, or transport of cellular and viral RNAs (16, 17). ADARs have a common modular domain organization that includes one to three dsRNA binding domains (dsRBDs) in their N-terminal region followed by a C-terminal catalytic domain (SI Appendix, Fig. S1A) (18).ADAR1 is expressed from two promotors, giving rise to a long, IFN-inducible version (ADAR1-i) and a constitutively expressed shorter version (ADAR1-c) (19). ADAR1-i harbors an NES in its unique N-terminal region (20) and is mostly cytoplasmic whereas ADAR1-c lacking the N-terminal NES is primarily nuclear (SI Appendix, Fig. S1B) (21). Both isoforms shuttle between the nucleus and cytoplasm (22, 23). Nuclear import of both ADAR1 versions is mediated by Trn1 via an NLS that overlaps the third dsRBD and shows no similarity to a PY-NLS (20, 22–24). Importantly, RNA-binding by this dsRBD interferes with Trn1 binding and nuclear import, thus constituting an RNA-regulated NLS (23).The dsRBD is a 65–70 amino acid domain that shape-specifically recognizes dsRNA (25–27). Structures of different dsRBDs have been determined, revealing a conserved αβββα fold with two α-helices packed against a three-stranded β-sheet (28, 29). dsRBD-mediated nucleocytoplasmic trafficking has been reported for ADAR1 (22, 23), but also for other dsRBD-containing proteins (30–36). Like for ADAR1, interaction with dsRNA has often been described to regulate the trafficking function of these dsRBDs. Importantly, the exact elements involved in the NLS activity of ADAR1-dsRBD3 still remain elusive. Further, how ADAR1-NLS that clearly differs from PY-NLSs interacts with Trn1 and how dsRNA binding competes with nuclear import remain unknown.To address these questions, we determined the solution structure of ADAR1-dsRBD3 by NMR spectroscopy. Besides a typical dsRBD fold, the structure reveals the presence of an additional N-terminal α-helix that brings the N- and C-terminal extremities in close proximity. We demonstrate that ADAR1-NLS is a bimodular NLS formed jointly by the combination of the N- and C-terminal fragments flanking ADAR1-dsRBD3. The dsRBD acts as a scaffold that helps to properly position the extensions for interaction with Trn1. We also provide a structural model showing how dsRNA binding can inhibit Trn1 binding and therefore prevent nuclear import.     

Robotic-assisted anorectal pull-through for anorectal malformations

Background/purpose

Many reports have addressed the feasibility and safety of using robotic surgery in children. To our knowledge, no published report has described the use of a surgical robot in the repair of anorectal malformations (ARMs).

Methods

Included children underwent robotic-assisted repair of ARMs with rectourethral fistula between April 2006 and March 2010 at King Khalid University Hospital, Riyadh, Saudi Arabia, using the da Vinci Surgical System. Their medical records were reviewed with respect to demographic data, associated anomalies, techniques and operative procedures, complications, outcomes, and follow-up.

Results

Five male infants (mean age, 6.6 months) underwent robotic-assisted repair of ARMs with rectourethral fistula using the Georgeson technique. The fistulae were divided and ligated in 4 patients and was left open in 1. All procedures were successfully completed without conversion to an open technique. One patient developed left-sided epididymo-orchitis postoperatively. All the patients had their colostomy closed. The follow-up ranged from 6 to 36 months. Fecal continence was difficult to assess in 2 patients. Two patients have voluntary bowel movements without soiling. One infant has fecal soiling and is on a laxative/enema for constipation.

Conclusions

Robotically assisted repair of ARMs with rectourethral fistula is feasible and safe. It offers a good alternative to the criterion standard, posterior sagittal anorectoplasty (PSARP), for repair of ARMs with rectourethral fistula. More patients and a longer follow-up period are needed for further evaluation of this novel approach.