ABSTRACT
Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC.
Subject(s)
Cyclin-Dependent Kinase 9 , Indolizines , Lung Neoplasms , Pyridinium Compounds , Small Cell Lung Carcinoma , Cyclin-Dependent Kinase 9/antagonists & inhibitors , Cyclin-Dependent Kinase 9/metabolism , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/pathology , Humans , Animals , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Cell Line, Tumor , Mice , Pyridinium Compounds/pharmacology , Pyridinium Compounds/therapeutic use , Indolizines/pharmacology , Cyclic N-Oxides/pharmacology , Apoptosis/drug effects , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic useABSTRACT
The detrusor-sphincter dyssynergia (DSD) is a common and significant problem for patients with spinal cord lesions. If not treated, DSD can lead to severe and potentially lethal complications (urinary tract infections and renal damage). BTX inhibits acetylcholine release at the neuromuscular junction, producing muscle chemical denervation in the site of injection. The aim of this preliminary study was to test the safety and the effects of BTX injection in the spastic urethral rhabdosphincter in patients with DSD. Five patients (3 M, 2 F; mean age 43 years, range 22-56) with DSD entered the study. Videourodynamic parameters were controlled before BTX injection at 10 days, at 3 and 6 months after infiltration. The aim of this preliminary study was to test the safety and the effects of BTX injection in the spastic urethral rhabdosphincter in patients with DSD. The post void residual urine volume, the maximum pressure of emptying and the maximum pressure of urethral closure are reported in Tab. II-III-IV. Patients reported subjective improvement of bladder emptying and improved quality of life. No adverse effects related to pharmacological activity of BTX or to infiltration procedures were observed.
Subject(s)
Botulinum Toxins, Type A/therapeutic use , Neuromuscular Agents/therapeutic use , Urinary Bladder, Neurogenic/therapy , Adult , Follow-Up Studies , Humans , Middle AgedABSTRACT
The Authors emphasize sonographic aspects of Renal Abscess in early phase and in proclaimed disease. The advent of the sonography and its extensive use marked an inversion of tendency in Perinephric Abscess evolution. So it is possible to point out small Abscesses and in early phase. Leukocytes tags Scintiscan and CT can confirm the diagnostic tentative.
Subject(s)
Abscess/diagnostic imaging , Pyelonephritis/diagnostic imaging , Humans , Radionuclide Imaging , Tomography, X-Ray Computed , UltrasonographyABSTRACT
Couple's study infertility sometimes need repeated hysterosalpingographical evaluations. In three cases the A.A. value echohysterosalpingography's utility. The echohysterosalpingography gives morphological and functional dates, is easy repeatable and the patients aren't exposed to ionizing radiations.
Subject(s)
Infertility, Female/diagnosis , Adult , Double-Blind Method , Female , Humans , Infertility, Female/diagnostic imaging , Radiography , UltrasonographyABSTRACT
Calcifying fibrous pseudotumor of epididymis is a rare neoplasia. The A.A. report echographical aspects about two clinical acses examined in 1993. Peculiar aspects of tumour are characterized by acoustic obstruction of the fibrous tissue and contextual iperechogenic spots, so to stimulate a calcific pseudocapsula. The A.A. revalue the echographical images after surgical exploration and discuss about differential diagnosis with TBC.