RNA sequencing steps toward the first line

• DNA is the sequence that codes for proteins.
• Messenger RNA is transcribed from the DNA sequence of genes and translated into protein.
• It can be difficult to predict how a change in the DNA sequence will affect messenger RNA and protein quantity and quality.
• DNA translocation changes can cause the joining of sequences from two different genes or different parts of the same gene.
• DNA sequencing is often used clinically to predict how DNA changes might affect proteins.
• Alternatively, RNA sequencing can be used as a more direct measure of the effect of DNA changes on the protein products.
• This sequencing is important for identifying changes in cancer that may indicate response to targeted therapy, prognosis, or diagnosis.

     

Selecting patients for early interdisciplinary rehabilitation during neurointensive care after moderate to severe traumatic brain injury

Background

Early interdisciplinary rehabilitation (EIR) in neurointensive care is a limited resource reserved for patients with moderate to severe traumatic brain injury (TBI) believed to profit from treatment. We evaluated how key parameters related to injury severity and patient characteristics were predictive of receiving EIR, and whether these parameters changed over time.

Methods

Among 1003 adult patients with moderate to severe TBI admitted over 72 h to neurointensive care unit during four time periods between 2005 and 2020, EIR was given to 578 and standard care to 425 patients. Ten selection criteria thought to best represent injury severity and patient benefit were evaluated (Glasgow Coma Scale, Head Abbreviated Injury Scale, New-Injury-Severity-Scale, intracranial pressure monitoring, neurosurgery, age, employment, Charlson Comorbidity Index, severe psychiatric disease, and chronic substance abuse).

Results

In multivariate regression analysis, patients who were employed (adjOR 1.99 [95% CI 1.41, 2.80]), had no/mild comorbidity (adjOR 3.15 [95% CI 1.72, 5.79]), needed neurosurgery, had increasing injury severity and were admitted by increasing time period were more likely to receive EIR, whereas receiving EIR was less likely with increasing age (adjOR 0.97 [95% CI 0.96, 0.98]) and chronic substance abuse. Overall predictive ability of the model was 71%. Median age and comorbidity increased while employment decreased from 2005 to 2020, indicating patient selection became less restrictive with time.

Conclusion

Injury severity and need for neurosurgery remain important predictors for receiving EIR, but the importance of age, employment, and comorbidity have changed over time. Moderate prediction accuracy using current clinical criteria suggest unrecognized factors are important for patient selection.     

Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.     

Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.     

The Cost-Effectiveness of Financial Incentives for Viral Suppression: HPTN 065 Study

Objective

To evaluate the cost-effectiveness of financial incentives for human immunodeficiency virus (HIV) viral suppression compared to standard of care.

Salivary gland hyalinizing clear‐cell carcinoma with cutaneous metastasis: A rare and deceptive tumor

Clear‐cell carcinoma (CCC) is an uncommon malignant tumor of minor salivary glands. It characteristically has a low‐grade morphology and a favorable outcome by most reports. An EWSR1‐ATF1 fusion can be detected in the majority of cases. We present a rare case of CCC, which had an aggressive course with the development of cutaneous metastases. Practicing dermatopathologists should be aware of this tumor given its low‐grade appearance and histopathologic resemblance to other primary cutaneous adnexal and metastatic neoplasms.     

Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors

This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition. This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD. Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses). Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.