Optical Nanosensor Passivation Enables Highly Sensitive Detection of the Inflammatory Cytokine Interleukin-6.

Interleukin-6 (IL-6) is known to play a critical role in the progression of inflammatory diseases such as cardiovascular disease, cancer, sepsis, viral infection, neurological disease, and autoimmune diseases. Emerging diagnostic and prognostic tools, such as optical nanosensors, experience challenges in translation to the clinic in part due to protein corona formation, dampening their selectivity and sensitivity. To address this problem, we explored the rational screening of several classes of biomolecules to be employed as agents in noncovalent surface passivation as a strategy to screen interference from nonspecific proteins. Findings from this screening were applied to the detection of IL-6 by a fluorescent-antibody-conjugated single-walled carbon nanotube (SWCNT)-based nanosensor. The IL-6 nanosensor exhibited highly sensitive and specific detection after passivation with a polymer, poly-l-lysine, as demonstrated by IL-6 detection in human serum within a clinically relevant range of 25 to 25,000 pg/mL, exhibiting a limit of detection over 3 orders of magnitude lower than prior antibody-conjugated SWCNT sensors. This work holds potential for the rapid and highly sensitive detection of IL-6 in clinical settings with future application to other cytokines or disease-specific biomarkers.

Stabilization of Prebiotic Vesicles by Peptides Depends on Sequence and Chirality: A Mechanism for Selection of Protocell-Associated Peptides.

Cells require oligonucleotides and polypeptides with specific, homochiral sequences to perform essential functions, but it is unclear how such oligomers were selected from random sequences at the origin of life. Cells were probably preceded by simple compartments such as fatty acid vesicles, and oligomers that increased the stability, growth, or division of vesicles could have thereby increased in frequency. We therefore tested whether prebiotic peptides alter the stability or growth of vesicles composed of a prebiotic fatty acid. We find that three of 15 dipeptides tested reduce salt-induced flocculation of vesicles. All three contain leucine, and increasing their length increases the efficacy. Also, leucine-leucine but not alanine-alanine increases the size of vesicles grown by multiple additions of micelles. In a molecular simulation, leucine-leucine docks to the membrane, with the side chains inserted into the hydrophobic core of the bilayer, while alanine-alanine fails to dock. Finally, the heterochiral forms of leucine-leucine, at a high concentration, rapidly shrink the vesicles and make them leakier and less stable to high pH than the homochiral forms do. Thus, prebiotic peptide-membrane interactions influence the flocculation, growth, size, leakiness, and pH stability of prebiotic vesicles, with differential effects due to sequence, length, and chirality. These differences could lead to a population of vesicles enriched for peptides with beneficial sequence and chirality, beginning selection for the functional oligomers that underpin life.

A percutaneous biliary anastomotic reconstruction for a failed Roux-en-Y hepaticojejunostomy in a patient with cholangiocarcinoma: A case report.

We hereby report a case of a novel percutaneous biliary anastomotic reconstruction of a disconnected segment 2 bile duct to the roux limb in a patient with cholangiocarcinoma suffering from bile leak post trisegmentectomy and roux-en-y hepaticojejunostomy. The patient was not a candidate for surgical reanastomosis and was suffering from repeated episodes of cholangitis prior to our intervention. We were successfully able to resolve the patient's biliary symptoms and need for an external biliary collection bag using our technique. The patient's case and the details of our intervention with relevant imaging is discussed. A review on the management of biliary leak following roux-en-y hepaticojejunostomy is also included.

Point-of-care anti-CD19 CAR T-cells for treatment of relapsed and refractory aggressive B-cell lymphoma.

Anti CD19 chimeric antigen receptor (CAR) T-cell therapy has transformed the care of relapsed and refractory aggressive B-cell lymphoma. However, financial toxicity and manufacturing time represent barriers to its widespread implementation. Study applicability, toxicity, and efficacy of a locally produced autologous CD19-directed CAR T-cell product were studied. We performed a phase 1b/2 clinical trial with a point-of-care (POC) CAR T-cell product that contains a CD28 costimulatory domain. Adult patients with aggressive B-cell lymphoma or transformed low-grade lymphoma who received at least 2 prior regimens were eligible. A total of 73 patients, with a median age of 49 years, met inclusion criteria. CAR T-cell production time from apheresis was 10 days (interquartile range 10-11), negating the need for bridging chemotherapy. Overall and complete response rates were 62.5% and 37.5%. Median progression-free and overall survival were 3.7 and 12.1 months, respectively. Overall and progression-free survival at 12 months were 52.1% (confidence interval [CI]: 40.8%-66.5%) and 40% (CI: 30%-53.7%), respectively. Patients who achieved response had longer progression-free and overall survival. Grade 3-4 cytokine release syndrome was observed in 9.5% of the patients, and immune effector cell-associated neurotoxicity syndrome grade 3-4 in 21.9%. No deaths occurred due to CAR T-cell toxicity. Fifteen patients (20%) underwent allogeneic stem cell transplantation at a median time of 60 days after CAR T-cell therapy; 8 were alive at last follow-up. Of the 6 patients who underwent the transplantation in complete response 2 deceased because of toxicity. POC CAR T-cells are a feasible therapeutic option in aggressive B-cell lymphoma. They provide good efficacy while minimizing production time and the need for bridging therapy.

Prebiotic Membranes and Micelles Do Not Inhibit Peptide Formation During Dehydration.

Cycles of dehydration and rehydration could have enabled formation of peptides and RNA in otherwise unfavorable conditions on the early Earth. Development of the first protocells would have hinged upon colocalization of these biopolymers with fatty acid membranes. Using atomic force microscopy, we find that a prebiotic fatty acid (decanoic acid) forms stacks of membranes after dehydration. Using LC-MS-MS (liquid chromatography-tandem mass spectrometry) with isotope internal standards, we measure the rate of formation of serine dipeptides. We find that dipeptides form during dehydration at moderate temperatures (55 °C) at least as fast in the presence of decanoic acid membranes as in the absence of membranes. Our results are consistent with the hypothesis that protocells could have formed within evaporating environments on the early Earth.

Novel Investigation of the Deep Band of the Lateral Plantar Aponeurosis and Its Relationship With the Lateral Plantar Nerve.

BACKGROUND: We describe a thick fascial band arising from the medial aspect of the lateral plantar aponeurosis diving deep into the forefoot crossing over a branch of the lateral plantar nerve. Because a review of current literature resulted in limited and outdated sources, we sought to first determine the frequency of this fascial band and the location where it crosses the lateral plantar nerve and, second, discuss the clinical applications these anatomical findings could have. METHODS: 50 pairs of cadaveric feet (n = 100) were dissected to investigate for presence of the fascial band and its interaction with the lateral plantar nerve. Images were taken of each foot with the fascial band. ImageJ was used to take 2 measurements assessing the relationship of the tuberosity of the base of the fifth metatarsal to where the nerve crossed deep to the fascial band. RESULTS: Overall, 38% of the feet possessed the fascial band. It was found unilaterally in 10 pairs and bilaterally in 14 pairs. On average, the point at which the lateral plantar nerve passed deep to the fascial band was 2.0 cm medial and 1.7 cm anterior to the tuberosity of the base of the fifth metatarsal. CONCLUSION: When present, the deep band of the lateral plantar aponeurosis (PA) was consistently found to be crossing the lateral plantar nerve. The discovery of the location where this most commonly occurs has not been previously reported and adds an interesting dimension that elevates an anatomical study to one that has clinical potential. CLINICAL RELEVANCE: The established target zone gives a precise location for where the relationship between the deep band of the lateral PA and the lateral plantar nerve exists when evaluating the foot. The target zone provides a potential springboard for future investigations concerning said relationship clinically.