UNASSIGNED: This study aimed to investigate the possible prognostic significance of interferon alpha-beta receptor subunit 2 (IFNAR2) and tyrosine kinase 2 (TYK2) expressions.
UNASSIGNED: We conducted a retrospective study including COVID-19 adult patients. All blood samples were collected before any interventions. The expressions of IFNAR2 and TYK2 were assessed using real-time PCR in venous blood samples of 54 cases and 56 controls. The transcript quantities of IFNAR2 and TYK2 genes were assessed using a Delta-Ct method.
UNASSIGNED: Our findings show no significant differences in gene expression levels for IFNAR2 and TYK2 between patients who required oxygen (O2) therapy and those who did not (p-value = 0.732 and p-value = 0.629, respectively). Likewise, there were no significant differences in IFNAR2 and TYK2 expressions between patients hospitalized for less than 7 days and those hospitalized for 7 days or more (p-value = 0.455 and p-value = 0.626, respectively). We also observed a weak correlation between IFNAR2 expression and CRP (p-value = 0.045, r = 0.192). There was a negative correlation between the expression levels of IFNAR2 and TYK2 transcripts in COVID-19 patients (p-value = 0.044; partial correlation coefficient = -0.283). Additionally, IFNAR2 and TYK2 were significantly downregulated in the COVID-19 group compared to healthy subjects (p-value = 0.002 and p-value = 0.028, respectively). However, neither IFNAR2 nor TYK2 expression was significantly different between the case subgroups based on COVID-19 severity. The IFNAR2 ΔΔCt (B = -0.184, 95% CI: -0.524-0.157, p-value = 0.275) and the TYK2 ΔΔCt (B = 0.114, 95% CI: -0.268-0.496, p-value = 0.543) were not found to be significant predictors of hospitalization duration. The area under the curve (AUC) for IFNAR2 expression is 0.655 (p-value = 0.005, 95% CI: 0.554-0.757), suggesting its poor discriminative value.
UNASSIGNED: We were unable to comment definitively on the prognostic power of IFNAR2 and TYK2 expressions in COVID-19 patients, and larger-scale studies are needed. The principal limitations of this study included the lack of longitudinal analysis and limited sample size.

The family of Janus Kinases (JAKs) associated with the JAK-signal transducers and activators of transcription signaling pathway plays a vital role in the regulation of various cellular processes. The conformational change of JAKs is the fundamental steps for activation, affecting multiple intracellular signaling pathways. However, the transitional process from inactive to active kinase is still a mystery. This study is aimed at investigating the electrostatic properties and transitional states of JAK1 to a fully activation to a catalytically active enzyme. To achieve this goal, structures of the inhibited/activated full-length JAK1 were modelled and the energies of JAK1 with Tyrosine Kinase (TK) domain at different positions were calculated, and Dijkstra\'s method was applied to find the energetically smoothest path. Through a comparison of the energetically smoothest paths of kinase inactivating P733L and S703I mutations, an evaluation of the reasons why these mutations lead to negative or positive regulation of JAK1 are provided. Our energy analysis suggests that activation of JAK1 is thermodynamically spontaneous, with the inhibition resulting from an energy barrier at the initial steps of activation, specifically the release of the TK domain from the inhibited Four-point-one, Ezrin, Radixin, Moesin-PK cavity. Overall, this work provides insights into the potential pathway for TK translocation and the activation mechanism of JAK1.

OBJECTIVE: The objective of this study was to clarify the detailed clinical course of recurrent clival chordoma and the outcomes of each treatment modality.
METHODS: A single-center retrospective analysis was conducted on patients seen for recurrent clival chordoma. The cohort was identified from those who underwent surgery, stereotactic radiosurgery, or proton therapy at the authors\' institution between 1990 and 2022.
RESULTS: A total of 95 recurrences in 40 patients with a median (interquartile range [IQR]) follow-up of 43 (18-79) months were identified. The median (IQR) age at the time of diagnosis was 48 (36-62) years, and 55% of patients were male. Twenty-three patients were treated with surgery followed by adjuvant radiation before the first recurrence. The median (range) number of recurrences per patient was 2 (1-8), and the median (IQR) time to the first recurrence was 29 (9-51) months. The recurrences were treated with one or more of the following therapies: surgery, radiation, systemic therapy, and laser interstitial thermal therapy (LITT). Surgery was performed for 44 recurrences in 25 patients. Radiation was used to treat 42 recurrences in 28 patients. Patients with recurrences treated with surgery plus radiation had the longest progression-free survival (PFS) (median [95% CI] overall survival [OS] 120 [0-245] months, p < 0.01, log-rank test). Patients with recurrences but without prior radiation had longer PFS than those patients with prior radiation. The median (95% CI) OS after the first recurrence was 68 (54-82) months, 5-year OS after the first recurrence was 48%, and 10-year OS was 27%. Multivariate Cox regression analysis showed that mortality after the first recurrence was significantly associated with no adjuvant radiation (HR 0.149, 95% CI 0.038-0.59, p = 0.0067), older age at the time of the first recurrence (HR 1.04, 95% CI 1.01-1.08, p = 0.021), and total number of recurrences (p = 0.032). Seven patients received systemic therapy, and the median (95% CI) OS of these patients since initiation of systemic therapy was 31 (11-51) months. Imatinib and/or nivolumab were used in 6 patients (15%). One patient (3%) was treated with LITT for his fourth recurrence.
CONCLUSIONS: Despite the aggressive nature of recurrent chordoma, 14 of 29 patients (48%) survived for more than 5 years after the initial recurrence using combined therapies. Multiple treatment options may contribute to the long-term survival of patients with this intractable tumor.

UNASSIGNED: Tirabrutinib, a second-generation inhibitor of Bruton\'s tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL) based on phase I/II studies in Japan. We previously reported the overall response rate and safety profile. We describe Karnofsky Performance Status (KPS) and the quality of life (QoL) in patients with r/r PCNSL receiving tirabrutinib based on more than 1-year follow-up data.
UNASSIGNED: Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with tirabrutinib once daily at a dose of 320, 480, or 480 mg under fasted conditions. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely EORTC QLQ-C30, EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L) along with KPS.
UNASSIGNED: Forty-four patients (mean age, 60 years [range 29-86]) were enrolled. The median follow-up period was 14.9 months (range, 1.4-27.7). The median KPS of the patients at baseline was 80.0 (range, 70-100), and this remained constant during the treatment. The global health status/QoL in the QLQ-C30 showed significant improvements from baseline through cycles 3-17 and remained relatively constant thereafter until cycle 23. Improvements were also seen in emotional functioning and constipation in the QLQ-C30 segments. Other items of QLQ-C30 and QLQ-BN20, EQ-5D visual analog scales, and EQ-5D index were maintained during the treatment.
UNASSIGNED: Tirabrutinib generally maintains KPS and QoL scores with some improvements in specific QoL items in patients with r/r PCNSL.

UNASSIGNED: c-MET is an important therapeutic target for various cancers; however, the People\'s Republic of China currently retails only one specific c-MET inhibitor. Our preclinical study has revealed the high selectivity of HS-10241 to suppress c-MET. This phase 1 study aims to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of the selective c-MET inhibitor (HS-10241) in patients with advanced solid tumors.
UNASSIGNED: Patients with locally advanced or metastatic solid tumors orally received a single or multiple dose of HS-10241 once daily or twice daily for 21 consecutive days, which included the following six regimens: 100 mg once daily, 200 mg once daily, 400 mg once daily, 600 mg once daily, 200 mg twice daily, and 300 mg twice daily. The treatment continued until disease progression, unacceptable toxicity, or treatment termination. The primary end point was the incidence of dose-limiting toxicity and maximal tolerated dose (MTD). Secondary end points included safety, tolerability, pharmacokinetics, and pharmacodynamics.
UNASSIGNED: A total of 27 patients with advanced NSCLC received HS-10241, and dose-limiting toxicity was observed in three patients after 600 mg once-daily HS-10241 treatment. For once-daily dosing, MTD was 400 mg, and for twice-daily dosing, the maximal safe escalated dose was 300 mg, and MTD was not reached. Nausea (48.1%, 13 of 27), fatigue (37.0%, 10 of 27), and anemia (33.3%, 9 of 27) are the three most frequent treatment-emergent adverse events. At 400 mg once daily, Css,max was 5076 ng/mL and steady state area under the curve was 39,998 h × ng/mL. Patients (n = 5) with positive MET (MET exon 14-skipping, MET amplified, and MET immunohistochemistry 3+) had confirmed partial responses (n = 1) or stable disease (n = 3), with a disease control rate of 80.0%.
UNASSIGNED: The selective c-MET inhibitor HS-10241 was well tolerated and had clinical activity in advanced NSCLC, especially in patients with positive MET. Furthermore, this study expounds on the therapeutic potential of HS-10241 in patients with cancer.

BACKGROUND: Imatinib is the gold standard for the treatment of all phases of Philadelphia positive Chronic Myeloid Leukemia (CML). During treatment, patients may develop cytopenia. We aimed to study the baseline characteristics and factors associated with cytopenia at a Nairobi Hospital.
METHODS: This was a retrospective case-control study of patients aged ≥18 years on follow-up at the Glivec International Patient Access Program (GIPAP) clinic from 2007 to 2015. The cases consisted of CML patients on imatinib who developed cytopenia. The controls were CML patients on imatinib who did not develop cytopenia. Baseline socio - demographic, clinical, hematologic, and molecular data were retrieved from patients\' files. Chi square or fishers\' exact tests were used to analyze for differences between cytopenia and no cytopenia. Binary logistic regressions were employed to identify relationships. Univariate and multivariate analyses were done to identify independent predictors of cytopenia. Odds ratios (OR) were presented including the 95% confidence intervals and respective p values.
RESULTS: A total of 201 patients were studied consisting of ninety-four (94) patients with cytopenia and 107 with no cytopenia. Among the entire population, males were 52, and 42% were aged 36-50 years. Sex, age, marital status, occupation and education level were similar between the cytopenia and no cytopenia groups. Among the 201 patients, 70% had symptoms for > 12 months before diagnosis, 78.6% had B symptoms at baseline, 80% had a moderate splenomegaly at baseline. Among patients with cytopenia, 40 and 37.4% developed cytopenia within 3 months and 3-6 months respectively after imatinib initiation. Baseline neutrophilia, neutropenia, anaemia, thrombocytosis, thrombocytopenia was found in 68, 11, 11, 23.5 and 11% respectively. Baseline hemoglobin, neutrophil and platelet level were significantly different between the cytopenia and the no cytopenia group. On univariable analysis, baseline anemia with hb < 7.9 g/dL (p = 0.002), neutropenia (p = 0.001), neutrophilia > 100,000/mm3 (p = 0.002) and thrombocytopenia (p = 0.001) increased the odds of developing cytopenia. On multivariable analysis, baseline anaemia (p value < 0.002), neutropenia (p value < 0.001), thrombocytopenia (p value, < 0.001) and thrombocytosis (p value, 0.033) increased the odds of developing cytopenia.
CONCLUSIONS: Odds of cytopenia were higher in presence of baseline cytopenia and thrombocytosis. Clinicians should have a high index of suspicion for these patients.

Kinases are considered as important signalling enzymes that illustrate 20% of the druggable genome. Human kinase family comprises >500 protein kinases and about 20 lipid kinases. Protein kinases are responsible for the mechanism of protein phosphorylation. These are necessary for regulation of various cellular activities including proliferation, cell cycle, apoptosis, motility, growth, differentiation, etc. Their deregulation leads to disruption of many cellular processes leading to different diseases most importantly cancer. Thus, kinases are considered as valuable targets in different types of cancer as well as other diseases. Researchers around the world are actively engaged in developing inhibitors based on distinct chemical scaffolds. Indole represents as a versatile scaffold in the naturally occurring and bioactive molecules. It is also used as a privileged scaffold for the target-based drug design against different diseases. This present article aim to review the applications of indole scaffold in the design of inhibitors against different tyrosine kinases such as epidermal growth factor receptors (EGFRs), vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), etc. Important structure activity relationships (SARs) of indole derivatives were discussed. The present work is an attempt to summarize all the crucial structural information which is essential for the development of indole based tyrosine kinase inhibitors with improved potency.

OBJECTIVE: In the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks by 44% in comparison with placebo, with manageable adverse events in most patients. We analyzed the efficacy and safety of nintedanib in patients of Asian race.
METHODS: Patients with SSc-ILD were randomized to receive nintedanib or placebo. The outcomes over 52 weeks were analyzed in Asian versus non-Asian patients.
RESULTS: Of the 288 patients in each treatment group, 62 (21.5%) in the nintedanib group and 81 (28.1%) in the placebo group were Asian; 90.2% of the Asian patients were enrolled in Asian countries. In the placebo group, the rate of FVC decline over 52 weeks was consistent between Asian and non-Asian patients (-99.9 and -90.6 mL/year, respectively). The effect of nintedanib on reducing the rate of FVC decline over 52 weeks was consistent between Asian (difference, 44.3 mL/year [95% CI: -32.8, 121.4]) and non-Asian patients (difference, 39.0 mL/year [95% CI: -5.1, 83.1]) (treatment-by-time-by-subgroup interaction, p = 0.91). Diarrhea was the most frequent adverse event and was reported in similar proportions of Asian and non-Asian patients in the nintedanib group (80.6% and 74.3%, respectively) and placebo group (28.4% and 32.9%, respectively).
CONCLUSIONS: In patients with SSc-ILD, nintedanib had a consistent benefit on slowing the progression of SSc-ILD in Asian and non-Asian patients, with a similar adverse event profile.
BACKGROUND: ClinicalTrials.gov NCT02597933.

UNASSIGNED: The prognosis for advanced hepatocellular carcinoma (HCC) remains clinically unsatisfying. Apatinib has proven to be a very effective treatment for advanced HCC in our previous retrospective study. Our aim in this study was to evaluate the efficacy, safety, and toxicity of apatinib in patients with advanced HCC.
UNASSIGNED: This single-arm, open-label phase II clinical trial enrolled patients with advanced HCC. These patients received apatinib, 500 mg once daily, until disease progression, unacceptable toxicity, consent withdrawal, or death. One treatment cycle consisted of 4 weeks of apatinib treatment. The response evaluation criteria in solid tumors (RECIST) was used to assess tumor response every 1-2 cycles. The primary endpoint was the objective response rate (ORR), while the secondary endpoints were the overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and toxicity.
UNASSIGNED: Between December 2016 and June 2018, 23 patients were enrolled in the study, 22 of whom were available for response evaluation. The cutoff date was August 10, 2018. The overall ORR and DCR were 30.4% and 65.2%, respectively. The median OS and PFS were 13.8 (95% CI: 5.3-22.3) and 8.7 (95% CI: 5.9-11.1) months, respectively. The most common treatment-related adverse events were proteinuria (39.1%), hypertension (34.8%), and hand-foot-skin reaction (34.8%).
UNASSIGNED: Apatinib showed robust clinical activity in patients with advanced HCC. Moreover, apatinib was safe to use, well tolerated, and had acceptable toxicity. (NCT03046979).

BACKGROUND: The nivolumab-ipilimumab combination provides an overall response rate of 42% in first-line metastatic treatment of clear cell renal carcinoma (mccRCC). To date, there is no robust predictive biomarker of response to immune checkpoint inhibitor (ICI). In addition, severe autoimmune disorders occur more frequently with ICI combination than with ICI alone. The objective of this study is to compare the efficacy of ICI alone or in combination in patients according to tumor molecular characteristics.
METHODS: Using a 35-gene expression mRNA signature, patients were divided into 4 molecular groups (1 to 4). Patients in groups 1 and 4 were randomized to receive nivolumab alone (arms 1A and 4A) or nivolumab plus ipilimumab for 4 injections followed by nivolumab alone (arms 1B and 4B). Patients in groups 2 and 3 were randomized to receive nivolumab plus ipilimumab followed by nivolumab alone (arms 2B and 3B) or a tyrosine kinase inhibitor (sunitinib or pazopanib at the investigator\'s choice (arms 2C and 3C)). The main objective is the overall response rate by treatment and molecular group.
CONCLUSIONS: BIONIKK is the first trial in mccRCC to study the personalization of treatment with ICI or TKI according to tumor molecular characteristics in mccRCC. This trial is the most appropriate to prospectively identify biomarkers of response to nivolumab used alone or in combination or TKI monotherapy in patients with mccRCC. NCT02960906.