Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy.

BACKGROUND: Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille's heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking. METHODS: The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action. RESULTS: We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration. CONCLUSIONS: Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.

Pedicled palmar intermetacarpal perforator flap for skin-graftless syndactyly release: Anatomical study and clinical application.

INTRODUCTION: Dorsal hand skin flaps have been described in order to avoid digit skin grafting in syndactyly release. Although these skin-graftless techniques present a lower rate of long term complications, they result in unsightly dorsal scarring and worse patient satisfaction. We describe a novel technique using an intermetacarpal palmar flap by performing an anatomic study and clinical application. MATERIALS AND METHODS: Ten colored-latex-injected fresh upper limbs were used to study the palmar cutaneous perforators to second to fourth intermetacarpal space skin flaps designed elliptical, its width extending from the center of each involved ray and measuring 40%-50% the length of the palm. RESULTS: The anatomical study revealed a mean 2.77 (range 1 to 4) cutaneous perforators originating from either the common or proper digital vessels for every intermetacarpal space and measuring 0.4 mm (range 0.3 to 0.5 mm) in diameter. CLINICAL APPLICATION: This flap, measuring a mean of 21.5 mm (range 20 to 23 mm) in length and 9.5 mm (range 9 to 10 mm) in width, was used to release simple syndactylies in three patients of mean age 24 months (range = 18-30 months). After skin incision, cutaneous septa to the digital canal were released to permit flap advancement to the web space. Cutaneous perforators were not dissected. Intra-operative palmar-flap advancement provided commissure coverage in all children with no skin grafts needed. Over a mean follow-up of 15 months, no complications occurred, mean palm scar VSS was 2.4 (range 2 to 3) while it was 3 (range 3 to 3) for the commissure scars. CONCLUSIONS: Skin-graftless syndactyly release using a palmar intermetacarpal flap seems both reliable and easy-to-perform. LEVEL OF EVIDENCE: Therapeutic IV.

Intravenous Foreign Body at the Hand: Case Report.

Intravenous foreign bodies following trauma to the hand are relatively uncommon with sparse reports of this condition being published in the literature. They have been reported to migrate as far as the thoracic cavity and the heart. In the following case report, we describe a case of an intravenous foreign body following hand trauma, and the treatment and potential complications are also discussed.

Controlling oncogenic KRAS signaling pathways with a Palladium-responsive peptide.

RAS oncoproteins are molecular switches associated with critical signaling pathways that regulate cell proliferation and differentiation. Mutations in the RAS family, mainly in the KRAS isoform, are responsible for some of the deadliest cancers, which has made this protein a major target in biomedical research. Here we demonstrate that a designed bis-histidine peptide derived from the αH helix of the cofactor SOS1 binds to KRAS with high affinity upon coordination to Pd(II). NMR spectroscopy and MD studies demonstrate that Pd(II) has a nucleating effect that facilitates the access to the bioactive α-helical conformation. The binding can be suppressed by an external metal chelator and recovered again by the addition of more Pd(II), making this system the first switchable KRAS binder, and demonstrates that folding-upon-binding mechanisms can operate in metal-nucleated peptides. In vitro experiments show that the metallopeptide can efficiently internalize into living cells and inhibit the MAPK kinase cascade.

One-stage Distal Interphalangeal Joint Fusion With External Fixator for the Treatment of Septic Joint Arthritis.

Septic joint arthritis in the small joints of the hand can be caused by penetrating trauma, ruptured ganglion cysts, or open joint dislocations, among others. The use of external fixation for the treatment of this condition has been reported in the past as a means of temporary joint distraction, or for secondary fusion procedures. In the present article, the authors describe a surgical technique involving the use of a low-cost external fixator for the primary arthrodesis of infected distal interphalangeal joints of the hand. The external fixator is fabricated with simple materials, threaded Kirshner wires, bone cement, and an insulin syringe, which the authors have used to fuse the distal interphalangeal joint primarily when destroyed by septic arthritis.

COVID-19 diagnosis by RT-qPCR in alternative specimens

BACKGROUND The high demand for adequate material for the gold standard reverse transcription real-time polymerase chain reaction (RT-qPCR)-based diagnosis imposed by the Coronavirus disease 2019 (COVID-19) pandemic, combined with the inherent contamination risks for healthcare workers during nasopharyngeal swab (NP) sample collection and the discomfort it causes patients, brought the need to identify alternative specimens suitable for the diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). OBJECTIVES The aim of this work was to compare saliva and gingival fluid swabs to NP swabs as specimens for RT-qPCR-based SARS-CoV-2 diagnosis. METHODS We compared gingival fluid swabs (n = 158) and saliva (n = 207) to the rayon-tipped NP swabs obtained from mild-symptomatic and asymptomatic subjects as specimens for RT-qPCR for SARS-CoV-2 detection. FINDINGS When compared to NP swabs, gingival fluid swabs had a concordance rate of 15.4% among positive samples, zero among inconclusive, and 100% among negative ones. For saliva samples, the concordance rate was 67.6% among positive samples, 42.9% among inconclusive, and 96.8% among negative ones. However, the concordance rate between saliva and NP swabs was higher (96.9%) within samples with lower cycle threshold (Ct) values (Ct > 10 ≤ 25). MAIN CONCLUSIONS Our data suggests that whereas gingival fluid swabs are not substitutes for NP swabs, saliva might be considered whenever NP swabs are not available or recommended.

Forearm Shortening Impact on Pronation and Supination.

Background: Shortening has been described to treat severely mangled extremities, replantations and nonunions. Outcomes after this procedure in the forearm are vaguely described. This study addresses how the forearm rotation is affected by: (1) location of the shortening; (2) the amount of the shortening at different locations. Methods: Nine fresh cadaveric forearms were dissected preserving intact proximal and distal radio ulnar joints and interosseous membrane. The widest point of the interosseous space and its location over the ulna were measured, defining the peak interosseous distance (PID) and the peak interosseous distance level (PIDL). Stabilization and fixation of the specimens were performed by using a platform and external fixators. Consecutive ostectomies were performed within one centimeter intervals at the distal, middle and proximal forearm thirds. A repeated measures mixed-effects (RMME) specific model was designed for the statistical analysis. Results: Before intervention, the average full forearm rotation was 157° (101-185), supination 80° (56-90)/pronation 77° (45-95). The average PID was 15.6 mm in supination and 12.5 mm in pronation. The PIDP were 52.2% and 58.3% of the ulna length in supination and pronation, respectively. The rotation lost were: middle third 5.31°/cm in supination and 6.12°/cm in pronation, distal third 1.62°/cm in supination and 2.20°/cm in pronation, the proximal third was not affected by up to 5 cm of shortening. Conclusions: These data suggest that shortening of the middle and distal third of the forearm might have more significant adverse effect on forearm rotation compared with the proximal third.

The First Dorsal Metacarpal Artery Flap Family: A Review.

Deep soft tissue injuries around the thumb can severely hinder hand function if not treated correctly. Many different surgical options have been described for the treatment of these serious lesions, including microsurgical flaps, such as toe to hand flaps, local flaps, and distant pedicled flaps. The first dorsal metacarpal artery family of flaps belongs to this last category. These flaps can be performed in different ways, as a racquet, as an island flap, and as a bilobed flap including the second metacarpal artery, among others. The aim of the following article is to review the basic concepts involved in the use of these flaps in reconstructive hand surgery.

Intramedullary Screws versus Kirschner Wires for Metacarpal Fixation, Functional, and Patient-Related Outcomes.

Purpose The purpose of our study is to compare the intramedullary fixation of metacarpal fractures with cannulated headless screws and antegrade Kirschner wires in terms of final total active motion, grip strength, patient-related outcomes, need for casting, and return to work times. Methods The authors performed a retrospective review of the hospital records. Thirty fractures were included in the study, 19 in the screw fixation group, and 11 in the Kirschner wire group. Grip strength, and total active motion, was measured at the latest follow-up for both the injured and contralateral hand. Pain was measured on the visual analog scale. Patients were requested to fill a Quick disabilities of the arm and hand score (DASH) questionnaire at the latest follow-up. Satisfaction was measured on a scale from 0 to 10. The time to return to work was quantified from the accident to the point when the patient was back to active duty. Postoperative casting time was also quantified. Results The authors did not find any differences between the two groups in total active motion, grip strength, pain, satisfaction, or Quick DASH scores. We did find a difference in the return to work and casting times; these appeared to be shorter in the screw group. Conclusion Due to the small number of cases, we have been unable to clearly conclude that there were any benefits in the application of one particular technique when compared with the other.

Comminuted Fracture of the Body of the Trapezium and Thumb Carpometacarpal Dislocation: A Particular Pattern.

Trapezium fractures are uncommon injuries. Our case is that of a thumb carpometacarpal joint dislocation associated to a partly comminuted fracture of the body of the trapezium. To the best of the authors' knowledge, this particular variation has not been previously reported in the indexed literature.

The Bilobed Racquet Flap or Extended Seagull Flap for Thumb Reconstruction: A Case Report.

The treatment of extensive soft tissue defects in the thumb with dorsal metacarpal artery flaps has been previously reported in the literature. Island flaps from the dorsum of the index and long fingers have been the subject of many reports and studies. However, when the defect involves the whole thumb, a 360° circumferential defect, standard first or second dorsal metacarpal artery flaps are usually insufficient. There are fewer reports on the use of bilobed flaps for this application and we have found no reports on the use of bilobed racquet flaps or extended seagull flaps as treatment for this condition. We report the salvage of a thumb degloving injury with use of a bilobed racquet flap.

Subcutaneous Injection of Oxyfluorfen Herbicide to the Forearm: Case Report.

Background Oxyfluorfen, a commercially available pesticide, commonly used for weed control in crop production, has been studied in terms of its toxicity, its carcinogenic properties, and its teratogenicity. We have found no reports, however, of the effects produced by an oxyfluorfen injection to the upper limb. Methods We present the case of a 40 years old psychiatric patient, who reportedly injected her forearm accidentally while fumigating her garden. She was treated with irrigation and open forearm fasciectomy. Results At 6 months, the patient had some tenderness at the scar; she wanted no further procedures done. Conclusion Oxyfluorfen appeared to produce a chemical burn to the forearm tissues including the fascia, removal of the chemical product, and a limited fasciectomy, resulted in a favorable outcome.

Ruthenation of Non-stacked Guanines in DNA G-Quadruplex Structures: Enhancement of c-MYC Expression.

Guanine quadruplexes (GQs) are compact four-stranded DNA structures that play a key role in the control of a variety of biological processes, including gene transcription. Bulky ruthenium complexes featuring a bipyridine, a terpyridine, and one exchangeable ligand ([Ru(terpy)(bpy)X]n+ ) are able to metalate exposed guanines present in the GQ of the c-MYC promoter region that are not involved in quadruplex base pairing. qRT-PCR and western-blot experiments indicated that the complexes promote a remarkable increase in the expression of this oncogene. We also show that exchangeable thioether ligands (X=RSR', Met) allow regulation of the metalating activity of the complex with visible light.

De novo design of a biologically active amyloid.

Most human proteins possess amyloidogenic segments, but only about 30 are associated with amyloid-associated pathologies, and it remains unclear what determines amyloid toxicity. We designed vascin, a synthetic amyloid peptide, based on an amyloidogenic fragment of vascular endothelial growth factor receptor 2 (VEGFR2), a protein that is not associated to amyloidosis. Vascin recapitulates key biophysical and biochemical characteristics of natural amyloids, penetrates cells, and seeds the aggregation of VEGFR2 through direct interaction. We found that amyloid toxicity is observed only in cells that both express VEGFR2 and are dependent on VEGFR2 activity for survival. Thus, amyloid toxicity here appears to be both protein-specific and conditional-determined by VEGFR2 loss of function in a biological context in which target protein function is essential.

Transition metal catalysis in the mitochondria of living cells.

The development of transition metal catalysts capable of promoting non-natural transformations within living cells can open significant new avenues in chemical and cell biology. Unfortunately, the complexity of the cell makes it extremely difficult to translate standard organometallic chemistry to living environments. Therefore, progress in this field has been very slow, and many challenges, including the possibility of localizing active metal catalysts into specific subcellular sites or organelles, remain to be addressed. Herein, we report a designed ruthenium complex that accumulates preferentially inside the mitochondria of mammalian cells, while keeping its ability to react with exogenous substrates in a bioorthogonal way. Importantly, we show that the subcellular catalytic activity can be used for the confined release of fluorophores, and even allows selective functional alterations in the mitochondria by the localized transformation of inert precursors into uncouplers of the membrane potential.

Trigger finger following partial flexor tendon laceration: Magnetic resonance imaging-assisted diagnosis.

INTRODUCTION: Post-traumatic trigger finger is considerably rarer than normal trigger finger. The diagnosis is usually made on a clinical basis. This can be obscured; however, by concurrent pathological conditions. We report a case of post-traumatic trigger finger in which diagnosis was aided by magnetic resonance imaging (MRI). PRESENTATION OF CASE: Our patient is a 32-year-old male who had a previous laceration with a subsequent surgery for infectious tenosynovitis. The MRI showed the impinging tendon tag. Surgical excision of the tag successfully solved the case. DISCUSSION: The use of imaging studies for the diagnosis of post-traumatic trigger finger has been previously reported, the authors described a variation on the contour of the pulley system. The full lacerated tendon tag can be seen on our patient's MRI. CONCLUSION: On this case, the use of MRI was a useful aid for the differential diagnosis of post-traumattic trigger finger.