With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. We have recently described a compound, MMV020291, as a ...specific inhibitor of red blood cell (RBC) invasion, and have generated analogues with improved potency. Here, we generated resistance to MMV020291 and performed whole genome sequencing of 3 MMV020291-resistant populations. This revealed 3 nonsynonymous single nucleotide polymorphisms in 2 genes; 2 in profilin (N154Y, K124N) and a third one in actin-1 (M356L). Using CRISPR-Cas9, we engineered these mutations into wild-type parasites, which rendered them resistant to MMV020291. We demonstrate that MMV020291 reduces actin polymerisation that is required by the merozoite stage parasites to invade RBCs. Additionally, the series inhibits the actin-1-dependent process of apicoplast segregation, leading to a delayed death phenotype. In vitro cosedimentation experiments using recombinant P. falciparum proteins indicate that potent MMV020291 analogues disrupt the formation of filamentous actin in the presence of profilin. Altogether, this study identifies the first compound series interfering with the actin-1/profilin interaction in P. falciparum and paves the way for future antimalarial development against the highly dynamic process of actin polymerisation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Peripheral neuropathy is a common dose-limiting side effect of paclitaxel. To date, there is no effective strategy to prevent paclitaxel-induced peripheral neuropathy. A recent small phase II study ...demonstrated the potential role of oral gabapentin in this setting. This phase III study is aimed to assess the efficacy of oral gabapentin in preventing paclitaxel-induced neuropathy.
To compare the efficacy of oral gabapentin with placebo in preventing clinically significant peripheral neuropathy (NCI CTCAEv5.0 grade 2 or higher) in patients receiving paclitaxel.
This is a randomized, placebo-controlled, double-blind, parallel-group superiority trial. The primary outcome is the development of grade 2 or higher chemotherapy-induced peripheral neuropathy. Secondary outcomes include any grade neuropathy, the percentage change in sensory nerve conduction velocities in peripheral nerves, time to development of any grade neuropathy, paclitaxel dose reductions and delays due to peripheral neuropathy, patient-reported outcomes, adverse events, and adherence to oral therapy. A total of 136 patients receiving paclitaxel will be randomly allocated (stratified by weekly vs. non-weekly administration) to receive either oral gabapentin or placebo till three weeks after the last dose of chemotherapy or occurrence of the primary outcome.
This study aims to find if oral gabapentin reduces the incidence of grade 2 or higher chemotherapy-induced peripheral neuropathy in patients receiving paclitaxel.
The trial is registered prospectively with the Clinical Trials Registry of India (CTRI/2022/02/040030) on April 4, 2022.
•Optimal staging procedure is the initial step.•Patients with high risk disease should be considered for adjuvant chemotherapy.•Paclitaxel and carboplatin (AUC 6) every 3 weeks is the standard.•Tumor ...grade is predictive of relapse free (RFS) and overall survival (OS).•5 yearRFS was 73 % and OS was 87 %.
One fifth of patients with epithelial ovarian cancers (EOC) present at an early stage (FIGO stage I & II). However, there is scarcity of literature on the outcomes and its predictors. The aim of the study was to assess relapse free survival (RFS), overall survival (OS) and its predictors in early stage EOC.
In this retrospectively study, we included all patients with early-stage EOC diagnosed between January 2010 and December 2018. Patients with synchronous malignancies were excluded. Clinical profile, clinico-pathological characteristics and treatment details were recorded. Patient underwent initial surgery followed by adjuvant chemotherapy in high-risk disease. Patients with stage IC, or stage II or clear cell histology or high-grade histology irrespective of stage/histological subtype were defined as high-risk disease. Fertility sparing surgery (FSS) unilateral salpingo-oopherectomy with complete surgical staging was performed in patient willing to preserve fertility. Primary objective was to assess RFS and OS in all patients with early stage EOC. Secondary objectives were to assess RFS and OS in early stage EOC with high-risk disease, predictors of RFS and OS, and outcomes of FSS. Survival probabilities were estimated according to Kaplan-Meier and compared by the log rank test. Cox's regression model was used to analyze the significance of various factors affecting relapse free survival (RFS) and overall survival (OS).
195 patients with early stage EOC were recruited with median age of 47 years (range, 16–80 years). FIGO stage I and stage II were seen in 72 % and 18 % patients respectively. Serous subtype was reported in 58 % and high-grade histology in 66 %. 184 patients (94.0%) underwent optimal staging surgery, including 27 (14%) with fertility sparing surgery (FSS). 133 (91.7 %) of 145 patients with high-risk disease received adjuvant chemotherapy (paclitaxel and carboplatin), while 12 (8.3 %) patients opted to remain on observation. At median follow up of 56 months (95 % CI, 46–64 months), 49 (25 %) patients relapsed including 3 of 27 (11.1 %) who underwent FSS, 18 patients died of progressive disease, while 31 patients were alive and disease free. Estimated OS at 5 years is 87.6 % (95 % CI 79.9–92.5) and RFS is 73.2 % (95 % CI 64.7–80.0). On multivariate analysis tumor grade was predictive of RFS (HR 2.9, p < 0.04) and OS (HR 9.4, p < 0.02).
This study confirms the excellent outcome for patients with early stage EOC. Histological grade of tumor is a significant predictor of OS and RFS. FSS is feasible in selected patients with early EOC.
The incidence of symptomatic brain metastasis at diagnosis in non-small-cell lung cancer (NSCLC) is 5%-10%, and up to 40% develop during the disease course. There is a paucity of data supporting the ...role of brain imaging at diagnosis in asymptomatic cases particularly from resource-constraint settings. Here, we present our experience of mandatory baseline brain imaging with contrast-enhanced computed tomography (CECT) scans of all patients with NSCLC.
This was a prospective observation study of patients with NSCLC with mandatory baseline brain CECT and a CNS examination. All histology proven patients with NSCLC diagnosed between January 2018 and October 2019 were included irrespective of stage.
A total of 496 patients were enrolled. The median age was 57 years (range, 23-84) with majority being males (75%) and smokers (66%). The prevalence of epidermal growth factor receptor mutations and anaplastic lymphoma kinase fusions was 33.4% and 12%, respectively. Brain imaging leads to upstaging in 7% cases. The prevalence of brain metastases was 21% (n = 104), with half being asymptomatic (51%). Factors associated with higher proportion of brain metastasis were young age (≤ 40 years), adenocarcinoma histology, poor Eastern Cooperative Oncology Group performance status (3 and 4), and high neutrophil-lymphocyte ratio (NLR) (> 2.5). After a median follow-up of 10.8 months (95% CI, 7.33 to 12.73), the median overall survival was 7.46 versus 12.76 months (hazard ratio 0.67; 95% CI, 0.46 to 0.96;
= .03) in patients with and without brain metastases, respectively. On multivariate analyses, high NLR and molecular graded prognostic assessment affected the overall survival significantly.
In our study, 21% of patients had brain metastasis at diagnosis detected with a mandatory baseline brain imaging with CECT. NLR and molecular graded prognostic assessment are significant predictors of survival in patients with brain metastasis.
Invasion of human erythrocytes by Plasmodium falciparum merozoites involves multiple interactions between host receptors and their merozoite ligands. Here we report human Cyclophilin B as a receptor ...for PfRhopH3 during merozoite invasion. Localization and binding studies show that Cyclophilin B is present on the erythrocytes and binds strongly to merozoites. We demonstrate that PfRhopH3 binds to the RBCs and their treatment with Cyclosporin A prevents merozoite invasion. We also show a multi-protein complex involving Cyclophilin B and Basigin, as well as PfRhopH3 and PfRh5 that aids the invasion. Furthermore, we report identification of a de novo peptide CDP3 that binds Cyclophilin B and blocks invasion by up to 80%. Collectively, our data provide evidence of compounded interactions between host receptors and merozoite surface proteins and paves the way for developing peptide and small-molecules that inhibit the protein-protein interactions, individually or in toto, leading to abrogation of the invasion process.
Serial patient-reported outcome (PRO) measurements in clinical practice are associated with a better quality of life and survival. Recording electronic PROs using smartphones is an efficient way to ...implement this. We aimed to assess the feasibility of the electronically filled Edmonton Symptom Assessment System (e-ESAS) scale in the lower-middle-income country (LMIC) setting.
Baseline clinical features and conventional paper-based ESAS (p-ESAS) were collected in newly diagnosed patients with solid organ tumors. Text message link was sent to these patients for filling e-ESAS. ESAS was categorized into physical, psychological, and total symptom domains. Scores were divided into none to mild (0-3) and moderate to severe (4-10). Intraclass correlation coefficients (ICCs) were used to determine the correlation between p-ESAS and e-ESAS. Multivariable logistic regression was used to identify independent factors affecting symptom burden.
Of 1,160 participants who filled out p-ESAS, 595 completed both e-ESAS and p-ESAS questionnaires and were included in the final analysis. Moderate to severe physical, psychological, and total symptom scores were seen in 39.8%, 40%, and 39% of participants. Tiredness and anxiety were the most common physical and psychological symptoms, respectively. ICCs between the p-ESAS and e-ESAS varied between 0.75 and 0.9. Total symptom scores were independently predicted by metastatic disease (odds ratio OR, 1.83; 95% CI, 1.26 to 2.67;
= .001) and a higher level of education (OR, 0.42; 95% CI, 0.25 to 0.72;
= .001).
Paper-based and electronically filled ESASs have good intraobserver reliability across individual symptoms and domain scores in a representative cohort at a tertiary care institute in the LMIC. This may help us incorporate e-ESAS in routine clinical care in the real-world setting with financial, infrastructural, and manpower limitations.
•In uterine cervical cancer, the currently used most common biomarkers for the diagnosis or prognosis are squamous cell carcinoma antigen (SCC-Ag) and CA125.•Raised serum level of SCC-Ag and CA125 ...are seen in 64% & 42.6% of squamous type of UCC respectively (1).•Serum level of HE4 was positive in 78%, while negative in 22% of UCC. It has sensitivity and specificity 78.12% and 88.89% respectively.•Serum level of HE4 has a far better result among available biomarkers in the diagnosis of UCC.•HE4 seems to be close to an ideal screening biomarker for uterine cervical cancer as described by Clarke-Pearson DL 2009 (2).•Serum level of HE4 may be considered a standard biomarker for cervical cancer.
Uterine cervical cancer (UCC) is the fourth most common health problem worldwide among women. Currently available biomarkers CA125, CA199, and CEA for diagnosis or prognostic evaluation of UCC have not got widespread acceptance.
Whole blood samples of 64 patients with UCC were collected along with 63 healthy females and tested for serum levels of HE4 (sHE4). A cut-off value for positive result 64.0 pmol/L was set. Statistical analysis of different clinical variables was done.
Serum level of HE4 has a significant role in the diagnosis of uterine cervical cancer. Its level increases with age, higher parity (P < 0.05), stage (P < 0.16), tumor size, and parametrial invasion. Negative result was seen with vaginal invasion, lymph node involvement & cases which had recurrence. Various histological types showed variable results. So the serum level of HE4 (sHE) level may play a role in the diagnosis & therapeutic monitoring of UCC. But the prognostic evaluation needs further studies.
sHE4 is useful in the diagnosis of cervical cancer, but its prognostic significance is under the question marks. It may be associated with higher values in higher stages. Higher parity of the patient is associated with higher level of HE4 in UCC.
An excessive amount of fat deposition in the body leads to obesity which is a complex disease and poses a generic threat to human health. It increases the risk of various other diseases like ...diabetes, cardiovascular disease, and multiple types of cancer. Genomic studies have shown that the expression of the fat mass obesity (
FTO
) gene was highly altered and identified as one of the key biomarkers for obesity. This study has been undertaken to investigate the mutational profile of the
FTO
gene and elucidates its effect on the protein structure and function. Harmful effects of various missense mutations were predicted using different independent tools and it was observed that all mutations were highly pathogenic. Molecular dynamics (MD) simulations were performed to study the structure and function of FTO protein upon different mutations and it was found that mutations decreased the structure stability and affected protein conformation. Furthermore, a protein residue network analysis suggested that the mutations affected the overall residues bonding and topology. Finally, molecular docking coupled with MD simulation suggested that mutations affected FTO substrate binding by changing the protein-ligand affinity. Hence, the results of this finding would help in an in-depth understanding of the molecular biology of the
FTO
gene and its variants and lead to the development of effective therapeutics against associated diseases and disorders.
The liver is one of the commonest sites of metastatic involvement in breast cancer, usually evident as focal lesions on imaging tests. Rarely, the pattern of metastatic spread is so diffuse that it ...remains radiologically occult. Such patients usually present with signs of hepatic insufficiency without any focal lesions on liver imaging. In such cases, liver biopsy is required to make a definitive diagnosis. We report a case of a 56-year-old postmenopausal woman with metastatic breast cancer who presented with subacute progressive liver failure. Repeated imaging of the liver was normal or non-descript. Liver biopsy finally established the diagnosis of intrasinusoidal metastases from breast cancer.
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