A phase Ib/II dose expansion study of subcutaneous sasanlimab in patients with locally advanced or metastatic non-small-cell lung cancer and urothelial carcinoma.

BACKGROUND: Sasanlimab is an antibody to the programmed cell death protein 1 receptor. We report updated data of subcutaneous sasanlimab in non-small-cell lung cancer (NSCLC) and urothelial carcinoma dose expansion cohorts from a first-in-human phase Ib/II study. PATIENTS AND METHODS: Patients were ≥18 years of age with NSCLC or urothelial carcinoma, and no prior immunotherapies, who progressed on or were intolerant to systemic therapy, or for whom systemic therapy was refused or unavailable. Patients received subcutaneous sasanlimab at 300 mg every 4 weeks (q4w). Primary objectives were to evaluate safety, tolerability, and clinical efficacy by objective response rate (ORR). RESULTS: Sixty-eight and 38 patients with NSCLC and urothelial carcinoma, respectively, received subcutaneous sasanlimab. Overall, sasanlimab was well tolerated; 13.2% of patients experienced grade ≥3 treatment-related adverse events. Confirmed ORR was 16.4% and 18.4% in the NSCLC and urothelial carcinoma cohorts, respectively. ORR was generally higher in patients with high programmed death-ligand 1 (PD-L1) expression (≥25%) and high tumor mutational burden (TMB; >75%). In the NSCLC and urothelial carcinoma cohorts, median progression-free survival (PFS) was 3.7 and 2.9 months, respectively; corresponding median overall survival (OS) was 14.7 and 10.9 months. Overall, longer median PFS and OS correlated with high PD-L1 expression and high TMB. Longer median PFS and OS were also associated with T-cell inflamed gene signature in the urothelial carcinoma cohort. CONCLUSIONS: Subcutaneous sasanlimab at 300 mg q4w was well tolerated with promising clinical efficacy observed. Phase II and III clinical trials of sasanlimab are ongoing to validate clinical benefit. Subcutaneous sasanlimab may be a potential treatment option for patients with NSCLC or urothelial carcinoma.

[Surgical treatment of children with generalized myasthenia]. / Khirurgicheskoe lechenie detei, bol'nykh generalizovannoi miasteniei.

The rich experience in the country in surgical treatment of children with generalized myasthenia has been analysed. The comparative analysis of various means of preoperative preparation is done. Stabilisation of myasthenical status is very important in the preoperative preparation, the use of steroid hormones is advocated for this purpose. The indications, contraindications, as well as the scope and optimal timing of surgery are formulated. Two types of clinical and immunomorphological changes are depicted in children with generalized myasthenia that are of certain prognostic value. The rating of risk factors, useful for prognosis of unfavorable results of surgery is proposed.

Solution structure of the catalytic domain of human stromelysin complexed with a hydrophobic inhibitor.

Stromelysin, a representative matrix metalloproteinase and target of drug development efforts, plays a prominent role in the pathological proteolysis associated with arthritis and secondarily in that of cancer metastasis and invasion. To provide a structural template to aid the development of therapeutic inhibitors, we have determined a medium-resolution structure of a 20-kDa complex of human stromelysin's catalytic domain with a hydrophobic peptidic inhibitor using multinuclear, multidimensional NMR spectroscopy. This domain of this zinc hydrolase contains a mixed beta-sheet comprising one antiparallel strand and four parallel strands, three helices, and a methionine-containing turn near the catalytic center. The ensemble of 20 structures was calculated using, on average, 8 interresidue NOE restraints per residue for the 166-residue protein fragment complexed with a 4-residue substrate analogue. The mean RMS deviation (RMSD) to the average structure for backbone heavy atoms is 0.91 A and for all heavy atoms is 1.42 A. The structure has good stereochemical properties, including its backbone torsion angles. The beta-sheet and alpha-helices of the catalytic domains of human stromelysin (NMR model) and human fibroblast collagenase (X-ray crystallographic model of Lovejoy B et al., 1994b, Biochemistry 33:8207-8217) superimpose well, having a pairwise RMSD for backbone heavy atoms of 2.28 A when three loop segments are disregarded. The hydroxamate-substituted inhibitor binds across the hydrophobic active site of stromelysin in an extended conformation. The first hydrophobic side chain is deeply buried in the principal S'1 subsite, the second hydrophobic side chain is located on the opposite side of the inhibitor backbone in the hydrophobic S'2 surface subsite, and a third hydrophobic side chain (P'3) lies at the surface.

Occurrence, solution structure and stability of DNA hairpins stabilized by a GA/CG helix unit.

The occurrence and NMR solution structure of a class of biloop hairpins containing the sequence 5'-CGXYAG are presented. These hairpins, which are variations on a sequence found in the reverse transcript of the human T-cell leukemia virus 2 (HLV2), show elevated melting points and high chemical stability toward denaturation by urea. Hairpins with the 5'-CGXYAG configuration have melting points 18-20 degrees higher than hairpins with 5'-CAXYGG or 5'-GGXYAC configurations. The identities of the looping bases, X and Y above, play a negligible role in determining the stability of this DNA hairpin stability. This is very different from G-A based loops in RNA, where the third base must be a purine for high stability [the GNRA loops; V.P. Antao, S.Y. Lai and I. Tinoco, Jr (1991) Nucleic Acids Res., 19, 5901-5905]. We show that these properties are associated with a four base helix unit that contains both a sheared GA base pair and a Watson-Crick CG base pair upon which it is stacked. As an understanding of the significance of AG base pairs has become increasingly important in the structural biology of nucleic acids, we compute an 0.7-0.9 A precision ensemble of NMR solution structures using iterative relaxation matrix methods. Calculations performed on NMR-derived structures indicate that neither base-base electrostatic interactions, nor base-solvent dispersive interactions, are significant factors in determining the observed differences in hairpin stability. Thus the stability of the 5'-CGXYAG configuration would appear to derive from favorable base-base London/van der Waals interactions.

[Diagnosis, surgical treatment and prognosis in patients with generalized myasthenia]. / Diagnostika, khirurgicheskoe lechenie i ego prognoz u bolnykh generalizovannoi miasteniei.

The work deals with the clinical analysis of the richest experience in the surgical treatment of patients with generalized myasthenia in the country. The efficacy of various methods for the diagnosis of affection of the thymus is studied comparatively. It is shown that for more effective diagnosis of neoplastic lesions of the thymus wider use of computerized and magneto-resonance tomography is expedient and that they must replace the insufficiently informative and invasive examination methods used today (pneumonodiastinography, phlebography, scintigraphy, etc.) which still form the basis for the system of diagnostic research in patients with myasthenia. The authors determined the indications and contraindications for, the optimum terms for undertaking the surgical intervention and its volume in neoplastic and nonneoplastic diseases of the thymus in adults and children. Comparative evaluation of various means of preoperative management was conducted. It is shown that to improve the patient's condition and stabilize the myasthenic status on the possibly minimal doses of anticholesteremic agents glucocorticoid hormones should be included in the complex of preoperative management. The indications for hormonotherapy were determined. The efficacy of plasmapheresis, radiotherapy, and glomectomy with denervation of the sinocarotid zone was evaluated and their place in the complex treatment of patients was determined. From study of the late-term results of treatment of a large group of patients (children, adults with a thymus) the main causes of unsuccessful surgical treatment of generalized myasthenia were identified and the concrete means of improving the results of treatment were planned. Two types of changes in the clinico-immuno-morphological values were revealed in patients with generalized myasthenia, differing evidently in pathogenesis. New clinico-immuno-morphological correlations and prognostic factors were discovered, and a method for prognosticating the effect of thymectomy was suggested. It is shown that splenectomy has a favorable effect in the most severe category of patients in unsuccessful operative and nonoperative treatment. The tactics of management of patients accepted in the clinic led to a uncomplicated course of the postoperative period in the majority of patients in the last years.

Interaction of lambda cro repressor with synthetic operator OR3 studied by competition binding with minor groove binders.

In the present work, we employ a combination of CD spectroscopy and gel retardation technique to characterize thermodynamically the binding of lambda phage cro repressor to a 17 base pair operator OR3. We have found that three minor groove-binding antibiotics, distamycin A, netropsin and sibiromycin, compete effectively with the cro for binding to the operator OR3. Among these antibiotics, sibiromycin binds covalently to DNA in the minor groove at the NH2 of guanine, whereas distamycin A and netropsin interact preferentially with runs of AT base pairs and avoid DNA regions containing guanine bases in the two polynucleotide strands. Only subtle DNA conformation changes are known to take place upon binding of these antibiotics. Both the CD spectral profiles and the results of the gel retardation experiments indicate that distamycin A and netropsin can displace cro repressor from the operator OR3. The binding of cro repressor to the OR3 is accompanied by considerable changes in CD in the far-UV region which appear to be attributed to a DNA-dependent structural transition in the protein. Spectral changes are also induced in the wavelength region of 270-290 nm. The CD spectral profile of the cro-OR3 mixture in the presence of distamycin A can be represented as a sum of the CD spectrum of the repressor-operator complex and spectrum of distamycin-DNA complex at the appropriate molar ratio of the bound antibiotic to the operator DNA (r). When r tends to the saturation level of binding the CD spectrum in the region of 270-360 nm approaches a CD pattern typical of complexes of the antibiotic with the free DNA oligomer. This suggests that simultaneous binding of cro repressor and distamycin A to the same DNA oligomer is not possible and that distamycin A and netropsin can be used to determine the equilibrium affinity constant of cro repressor to the synthetic operator from competition-type experiments. The binding constant of cro repressor to the OR3 is found to be (6 +/- 1).10(6)M-1 at 20 degrees C in 10 mM sodium cacodylate buffer (pH 7.0) in the presence of 0.1 M NH4F.

[Diagnosis and surgical treatment of myasthenia gravis in childhood]. / Diagnostika i khirurgicheskoe lechenie miastenii v detskom vozraste.

Thirty-year experience in surgical treatment of myasthenia in children and adolescents (175 patients) is generalized. It provides evidence of delayed recognition of this disease in many patients and of prolonged, often ineffective nonoperative treatment. Operation for thymectomy should be one of the main methods for the management of myasthenia in children. Operative treatment is indicated in a disease of moderate severity or in a severe course of myasthenia, particularly in patients with the first type of immunomorphological changes. It is important to amend the myasthenic disorders before the operation by means of maximally possible doses of anticholinesterases with addition of corticosteroids, whenever necessary. Whatever the method of treatment chosen, the patients must be kept under skilled dynamic control. Excellent and good late-term results were produced in 84.6% of cases.

[Intraoperative ultrasonographic examination in surgery of the biliary tract]. / Intraoperatsionnoe ul'trazvukovoe issledovanie v khirurgii zhelchnykh putei.

The diagnostic value of intraoperative ultrasonic examination (IUSE) in surgery on the biliary tract was shown from analysis of the literature and the authors' experience. IUSE in more than 300 patients demonstrated a high resolving power in the diagnosis of choledocholithiasis and the absence of radiation load, allergic reactions and complications. In comparison of IUSE with intraoperative cholangiography in the diagnosis of stones in the gallbladder the total efficacy of the methods was 98.2% and 92.6%, respectively. IUSE has no side effects, is a simpler and cheaper method of examination, and allows goal-oriented removal of stones from the biliary tract. It is shown that with accumulation of experience in IUSE the performance of intraoperative cholangiography can be brought to the minimum.

Two-stage thermal unfolding of [Cys55]-substituted Cro repressor of bacteriophage lambda.

It has been shown by scanning calorimetry and 1H NMR spectroscopy that thermal denaturation of mutant lambda phage cro repressor in which Val55 was substituted for Cys, proceeds in 2 stages in contrast to the wild type protein. At neutral pH values, an additional cooperative transition has been observed at about 100 degrees C. Calorimetric measurements on the mutant and its tryptic fragment lead to the conclusion that the two-stage character of thermal unfolding of the mutant is due to a disruption of an additional cooperative domain in the dimer molecule which is stabilized by the S-S crosslink.

[Complete assignment of signals in 1D and 2D H-NMR spectra of a 17-member oligonucleotide, a model symmetrical analog of lambda operators]. / Polnoe otnesenie signalov v 1D i 2D H-IaMR-spektrakh 17-chlennogo oligonukleotida - model'nogo simmetrichnogo analoga lambda-operatorov.

A synthetic analog of lambda phage operators, a symmetric duplex of oligonucleotides, was studied by 1H NMR at 400 MHz. Signals in the spectrum of imino protons of the duplex in H2O were assigned based on the results of NOE experiments and temperature dependences. Resonance assignment of the non-exchangeable protons of bases and deoxyribose was performed by analysing the NOESY spectrum obtained in the single experiment. The results indicate that the major part of the duplex has a conformation similar to the B-form of DNA, and the region of the central non-complementary base pair exhibits deviations from the regular structure.