therapeutic success
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2022 ◽  
Vol 8 ◽  
Author(s):  
Yi-Li Zheng ◽  
Xuan Su ◽  
Yu-Meng Chen ◽  
Jia-Bao Guo ◽  
Ge Song ◽  
...  

Neuropathic pain (NP) is poorly managed, and in-depth mechanisms of gene transcriptome alterations in NP pathogenesis are not yet fully understood. To determine microRNA-related molecular mechanisms of NP and their transcriptional regulation in NP, PubMed, Embase, Web of Science and CINAHL Complete (EBSCO) were searched from inception to April 2021. Commonly dysregulated miRNAs in NP were assessed. The putative targets of these miRNAs were determined using TargetScan, Funrich, Cytoscape and String database. A total of 133 literatures containing miRNA profiles studies and experimentally verify studies were included. Venn analysis, target gene prediction analysis and functional enrichment analysis indicated several miRNAs (miR-200b-3p, miR-96, miR-182, miR-183, miR-30b, miR-155 and miR-145) and their target genes involved in known relevant pathways for NP. Targets on transient receptor potential channels, voltage-gated sodium channels and voltage-gated calcium channels may be harnessed for pain relief. A further delineation of signal processing and modulation in neuronal ensembles is key to achieving therapeutic success in future studies.


Author(s):  
Katharina Joechle ◽  
Jessica Guenzle ◽  
Stefan Utzolino ◽  
Stefan Fichtner-Feigl ◽  
Lampros Kousoulas

Abstract Purpose Although Ogilvie’s syndrome was first described about 70 years ago, its etiology and pathogenesis are still not fully understood. But more importantly, it is also not clear when to approach which therapeutic strategy. Methods Patients who were diagnosed with Ogilvie’s syndrome at our institution in a 17-year time period (2002–2019) were included and retrospectively evaluated regarding different therapeutical strategies: conservative, endoscopic, or surgical. Results The study included 71 patients with 21 patients undergoing conservative therapy, 25 patients undergoing endoscopic therapy, and 25 patients undergoing surgery. However, 38% of patients (n = 8) who were primarily addressed for conservative management failed and had to undergo endoscopy or even surgery. Similarly, 8 patients (32%) with primarily endoscopic treatment had to proceed for surgery. In logistic regression analysis, only a colon diameter ≥ 11 cm (p = 0.01) could predict a lack of therapeutic success by endoscopic treatment. Ninety-day mortality and overall survival were comparable between the groups. Conclusion As conservative and endoscopic management fail in about one-third of patients, a cutoff diameter ≥ 11 cm may be an adequate parameter to evaluate surgical therapy.


2022 ◽  
Vol 6 (1) ◽  
pp. 01-06
Author(s):  
Khin Phyu Pyar ◽  
Sai Aik Hla ◽  
Win Myint ◽  
Win Kyaw Shwe ◽  
Soe Win Hlaing ◽  
...  

A 58 year old man was brought to hospital in state of deep coma following severe headache for one day. His GCS was 3/15 and had flaccid all 4 limbs with equivocal planter response on both sides on arrival. NECT head showed acute subdural haemorrhage with surrounding cerebral oedema, mid-line shift and corning of brain stem. After giving mannitol and dexamethasone, four hours later, he became fully conscious and orientated; his motor power returned to normal. He was on warfarin 3mg daily for rheumatic mitral valvular heart disease with atrial fibrillation and his INR on arrival was 3.5. He had intractable hiccups once he regained consciousness. Both pharmacological and non-pharmacological measures were tried for distressing hiccups; there was no therapeutic success. His hiccups disappeared completely only after removing the haematoma by burr hole surgery.


2022 ◽  
Author(s):  
Erika Y. Faraoni ◽  
Nirav C. Thosani ◽  
Baylee O'Brien ◽  
Lincoln N. Strickland ◽  
Victoria Y. Mota ◽  
...  

Background and Aims: Pancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to therapy. A major contributing factor to therapeutic failure is profound desmoplasia and a well-documented hypoxic tumor microenvironment (TME). In PDAC, several therapeutic approaches, including chemotherapy and radiation alone or combined with immune checkpoint inhibitors, have shown minimal therapeutic success, placing an imperative need for the discovery and application of innovative treatments. Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) is a promising immunomodulator therapy for PDAC. In this work, we hypothesized RFA promotes local and systemic stromal and immunomodulating effects that can be identified for new combination therapeutic strategies. Methods: To test our hypothesis, a syngeneic PDAC mouse model was performed by symmetrically injecting 100k murine KPC cells in bilateral flanks of C57BL/6 female mice. RFA treatment initiated when tumors reached 200-500 mm3 and was performed only in the right flank. The left flank tumor (non-RFA contralateral side) was used as a paired control for further analysis. Results: RFA promoted a significant reduction in tumor growth rate 4 days after treatment in RFA treated and non-RFA side contralateral tumors from treated mice when compared to controls. Histological analysis revealed a significant increase in expression of cleaved Caspase3 in RFA treated tumors. In addition, collagen deposition and CD31+ cells were significantly elevated in RFA side and non-RFA contralateral tumors from RFA treated mice. Proteome profiling showed changes in C5a and IL-23 in RFA responsive tumors, indicating a role of RFA in modulating intratumoral inflammatory responses. Conclusions: These data indicate RFA promotes local and systemic anti-tumor responses in a syngeneic mouse model of PDAC implicating RFA treatment for local tumors as well as metastatic disease. Keywords: tumor associated macrophages; IL-23; tumor vasculature; ablation induced necrosis


2022 ◽  
Vol 12 (1) ◽  
pp. 46-56
Author(s):  
Marc Spielmanns ◽  
Sebastian Schildge ◽  
Jens Peter Diedrich ◽  
Arschang Valipour

Health-related quality of life (HRQoL) in patients with moderate to severe chronic obstructive pulmonary disease (COPD) is often reduced by high symptom burden and frequent exacerbations. So far, data on therapeutic success in Swiss COPD patients receiving dual bronchodilation therapy as COPD maintenance treatment are limited. Data from a recently published, non-interventional study on clinical benefit after the start of combined tiotropium–olodaterol treatment were analyzed focusing on Swiss patients compared to the overall cohort including patients from various European countries. Demographic data on the changes in Clinical COPD Questionnaire (CCQ) for the assessment of HRQoL in correlation to symptoms and the number of exacerbations, as well as physician’s global assessment (PGE), were evaluated 6 weeks after treatment start. In Switzerland (n = 61), significantly more patients had comorbidities and exacerbations but showed less symptoms compared to the overall cohort (n = 4639). HRQoL improved in both cohorts, with a negative correlation to symptom burden and number of exacerbations in the overall cohort. PGE scores improved after 6 weeks with a better general condition at baseline in Swiss patients (PGE score 4/5: 68.9% [Swiss cohort] vs. 49.0% [overall cohort]. Despite significant differences regarding the presence of symptoms and exacerbations, therapeutic success was similar in both patient groups. Highly symptomatic patients benefited mostly from tiotropium–olodaterol treatment.


2022 ◽  
Vol 12 ◽  
Author(s):  
Stefan Schob ◽  
Richard Brill ◽  
Eberhard Siebert ◽  
Massimo Sponza ◽  
Marie-Sophie Schüngel ◽  
...  

Background: Treatment of cerebral aneurysms using hemodynamic implants such as endosaccular flow disruptors and endoluminal flow diverters has gained significant momentum during recent years. The intended target zone of those devices is the immediate interface between aneurysm and parent vessel. The therapeutic success is based on the reduction of aneurysmal perfusion and the subsequent formation of a neointima along the surface of the implant. However, a subset of aneurysms–off-centered bifurcation aneurysms involving the origin of efferent branches and aneurysms arising from peripheral segments of small cerebral vessels–oftentimes cannot be treated via coiling or implanting a hemodynamic implant at the neck level for technical reasons. In those cases, indirect flow diversion–a flow diverter deployed in the main artery proximal to the parent vessel of the aneurysm–can be a viable treatment strategy, but clinical evidence is lacking in this regard.Materials and Methods: Five neurovascular centers contributed to this retrospective analysis of patients who were treated with indirect flow diversion. Clinical data, aneurysm characteristics, anti-platelet medication, and follow-up results, including procedural and post-procedural complications, were recorded.Results: Seventeen patients (mean age: 60.5 years, range: 35–77 years) with 17 target aneurysms (vertebrobasilar: n = 9) were treated with indirect flow diversion. The average distance between the flow-diverting stent and the aneurysm was 1.65 mm (range: 0.4–2.4 mm). In 15/17 patients (88.2%), perfusion of the aneurysm was reduced immediately after implantation. Follow-ups were available for 12 cases. Delayed opacification (OKM A3: 11.8%), reduction in size (OKM B1-3: 29.4%) and occlusion (D1: 47.1%) were observable at the latest investigation. Clinically relevant procedural complications and adverse events in the early phase and in the late subacute phase were not observed in any case.Conclusion: Our preliminary data suggest that indirect flow diversion is a safe, feasible, and effective approach to off-centered bifurcation aneurysms and distant small-vessel aneurysms. However, validation with larger studies, including long-term outcomes and optimized imaging, is warranted.


PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1009989
Author(s):  
Michelle Ledru ◽  
Caitlin A. Clark ◽  
Jeremy Brown ◽  
Shilpi Verghese ◽  
Sarah Ferrara ◽  
...  

Ionizing radiation (IR) is used to treat half of all cancer patients because of its ability to kill cells. IR, however, can induce stem cell-like properties in non-stem cancer cells, potentiating tumor regrowth and reduced therapeutic success. We identified previously a subpopulation of cells in Drosophila larval wing discs that exhibit IR-induced stem cell-like properties. These cells reside in the future wing hinge, are resistant to IR-induced apoptosis, and are capable of translocating, changing fate, and participating in regenerating the pouch that suffers more IR-induced apoptosis. We used here a combination of lineage tracing, FACS-sorting of cells that change fate, genome-wide RNAseq, and functional testing of 42 genes, to identify two key changes that are required cell-autonomously for IR-induced hinge-to-pouch fate change: (1) repression of hinge determinants Wg (Drosophila Wnt1) and conserved zinc-finger transcription factor Zfh2 and (2) upregulation of three ribosome biogenesis factors. Additional data indicate a role for Myc, a transcriptional activator of ribosome biogenesis genes, in the process. These results provide a molecular understanding of IR-induced cell fate plasticity that may be leveraged to improve radiation therapy.


Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 109
Author(s):  
Zoltán Somogyi ◽  
Patrik Mag ◽  
Dóra Kovács ◽  
Ádám Kerek ◽  
Pál Szabó ◽  
...  

Florfenicol is a member of the phenicol group, a broad-spectrum antibacterial agent. It has been used for a long time in veterinary medicine, but there are some factors regarding its pharmacokinetic characteristics that have yet to be elucidated. The aim of our study was to describe the pharmacokinetic profile of florfenicol in synovial fluid and plasma of swine after intramuscular (i.m.) administration. In addition, the dosage regimen of treatment of arthritis caused by S. suis was computed for florfenicol using pharmacokinetic/pharmacodynamic (PK/PD) indices. As the first part of our investigation, the pharmacokinetic (PK) parameters of florfenicol were determined in the plasma and synovial fluid of six pigs. Following drug administration (15 mg/kgbw, intramuscularly), blood was drawn at the following times: 10, 20, 30, 40, 50 and 60 min, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48 and 72 h; synovial fluid samples were taken after 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h. The concentration of florfenicol was determined by a validated liquid chromatography-mass spectrometry (LC-MS/MS) method via multiple reaction monitoring (MRM) modes. As the second part of our research, minimum inhibitory concentration (MIC) values of florfenicol were determined in 45 S. suis strains isolated from clinical samples collected in Hungary. Furthermore, a strain of S. suis serotype 2 (SS3) was selected, and killing-time curves of different florfenicol concentrations (0.5 µg/mL, 1 µg/mL and 2 µg/mL) were determined against this strain. Peak concentration of the florfenicol was 3.58 ± 1.51 µg/mL in plasma after 1.64 ± 1.74 h, while it was 2.73 ± 1.2 µg/mL in synovial fluid 3.4 ± 1.67 h after administration. The half-life in plasma was found to be 17.24 ± 9.35 h, while in synovial fluid it was 21.01 ± 13.19 h. The area under the curve (AUC24h) value was 54.66 ± 23.34 μg/mL·h for 24 h in plasma and 31.24 ± 6.82 μg/mL·h for 24 h in synovial fluid. The drug clearance scaled by bioavailability (Cl/F) in plasma and synovial fluid was 0.19 ± 0.08 L/h/kg and 0.29 ± 0.08 L/h/kg, respectively. The mean residence time (MRT) in plasma and synovial fluid was 24.0 ± 13.59 h and 27.39 ± 17.16 h, respectively. The steady-state volume of distribution (Vss) in plasma was calculated from Cl/F of 0.19 ± 0.08 L/h/kg, multiplied by MRT of 24.0 ± 13.59 h. For the PK/PD integration, average plasma and synovial fluid concentration of florfenicol was used in a steady-state condition. The obtained MIC50 value of the strains was 2.0 µg/mL, and MIC90 proved to be 16.0 µg/mL. PK/PD integration was performed considering AUC24h/MIC breakpoints that have already been described. This study is the first presentation of the pharmacokinetic behavior of florfenicol in swine synovia as well as a recommendation of extrapolated critical MICs of S. suis for therapeutic success in the treatment of S. suis arthritis in swine, but it should be noted that this requires a different dosage regimen to that used in authorized florfenicol formulations.


2021 ◽  
Vol 84 (1) ◽  
Author(s):  
Guim Aguadé-Gorgorió ◽  
Stuart Kauffman ◽  
Ricard Solé

AbstractPhenotypic switching in cancer cells has been found to be present across tumor types. Recent studies on Glioblastoma report a remarkably common architecture of four well-defined phenotypes coexisting within high levels of intra-tumor genetic heterogeneity. Similar dynamics have been shown to occur in breast cancer and melanoma and are likely to be found across cancer types. Given the adaptive potential of phenotypic switching (PHS) strategies, understanding how it drives tumor evolution and therapy resistance is a major priority. Here we present a mathematical framework uncovering the ecological dynamics behind PHS. The model is able to reproduce experimental results, and mathematical conditions for cancer progression reveal PHS-specific features of tumors with direct consequences on therapy resistance. In particular, our model reveals a threshold for the resistant-to-sensitive phenotype transition rate, below which any cytotoxic or switch-inhibition therapy is likely to fail. The model is able to capture therapeutic success thresholds for cancers where nonlinear growth dynamics or larger PHS architectures are in place, such as glioblastoma or melanoma. By doing so, the model presents a novel set of conditions for the success of combination therapies able to target replication and phenotypic transitions at once. Following our results, we discuss transition therapy as a novel scheme to target not only combined cytotoxicity but also the rates of phenotypic switching.


Author(s):  
Osamah Omar Almostaffa, Hassan Zaizafoun, Milad Antonios Osamah Omar Almostaffa, Hassan Zaizafoun, Milad Antonios

    Objective: The aim of this study is to evaluate the indications, findings, and complications of performing Endoscopic Retrograde Cholangiopancreatography (ERCP). Patients and Methods: A Prospective Observational Descriptive study conducted for the period from January 2020 to January 2021, 167 consecutive ERCP were performed at Tishreen University Hospital in Lattakia-Syria. Results: The median age was 58 years, 59.30% of patients were female. The most common indications for ERCP were common bile duct stones (44.9%) and obstructive jaundice (44.3%). The median number of attempts for cannulation was 2 counts, and 74.3% of the procedures were graded as with difficulty grade 1. The most common abnormal findings were common bile duct dilation (50.3%) and bile duct stones (43.7%). The most therapeutic endoscopic interventions were sphincterotomy (64.7%) and stone extraction balloons (68.9%). The therapeutic success rate was 93.5% with repeated the procedure and complications occurred in (10.8%) of patients. The most frequent complication was mild pancreatitis (6%). Death was reported in five cases (3%), one of them (0.6%) was due to ERCP. Conclusion: ERCP is a potential risk for complications, so physicians should be adept at recognizing and treating any complications as soon as they arise.


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