Prediction of biomarkers and therapeutic combinations for anti-PD-1 immunotherapy using the global gene network association

Owing to a lack of response to the anti-PD1 therapy for most cancer patients, we develop a network approach to infer genes, pathways, and potential therapeutic combinations that are associated with tumor response to anti-PD1. Here, our prediction identifies genes and pathways known to be associated with anti-PD1, and is further validated by 6 CRISPR gene sets associated with tumor resistance to cytotoxic T cells and targets of the 36 compounds that have been tested in clinical trials for combination treatments with anti-PD1. Integration of our top prediction and TCGA data identifies hundreds of genes whose expression and genetic alterations that could affect response to anti-PD1 in each TCGA cancer type, and the comparison of these genes across cancer types reveals that the tumor immunoregulation associated with response to anti-PD1 would be tissue-specific. In addition, the integration identifies the gene signature to calculate the MHC I association immunoscore (MIAS) that shows a good correlation with patient response to anti-PD1 for 411 melanoma samples complied from 6 cohorts. Furthermore, mapping drug target data to the top genes in our association prediction identifies inhibitors that could potentially enhance tumor response to anti-PD1, such as inhibitors of the encoded proteins of CDK4, GSK3B, and PTK2.

Metabolic Implications of Immune Checkpoint Proteins in Cancer

Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.

Respiratory alkalosis provokes spike-wave discharges in seizure-prone rats

Hyperventilation reliably provokes seizures in patients diagnosed with absence epilepsy. Despite this predictable patient response, the mechanisms that enable hyperventilation to powerfully activate absence seizure-generating circuits remain entirely unknown. By utilizing gas exchange manipulations and optogenetics in the WAG/Rij rat, an established rodent model of absence epilepsy, we demonstrate that absence seizures are highly sensitive to arterial carbon dioxide, suggesting that seizure-generating circuits are sensitive to pH. Moreover, hyperventilation consistently activated neurons within the intralaminar nuclei of the thalamus, a structure implicated in seizure generation. We show that intralaminar thalamus also contains pH-sensitive neurons. Collectively, these observations suggest that hyperventilation activates pH-sensitive neurons of the intralaminar nuclei to provoke absence seizures.

Oral Candidiasis with Subcutaneaous Emphyema Associated With Sari Following Post COVID 19: A Case Report

Background: Over the last few decades, the covid 19 has increased all over the world. More issues are likely to be observed as covid 19 rate increases. The major cause of morbidity and mortality is infection. Oral Candidiasis With Subcutaneaous Emphyema and SARI are very rare complications in Covid 19 patient. The final cause is infection, but sometimes it causes due to allergic or inflammatory reaction of the drugs. If it occurs after post covid 19 then creates very serious issues with the peoples health. Case Presentation: Here we are mentioning a very rare case of Oral Candidiasis With Subcutaneaous Emphyema and SARI after Covid 19 positive patient. In this case, on physical examination and investigation, it was found that, after covid 19 patient has developed Oral Candidiasis, Subcutaneous Emphysema , severe breathlessness, cough, fever, nausea, vomiting, throat infection and loss of appetide. To overcome this sudden issue, emergency exploratory medical and surgical treatment was done. During Covid 19 treament her HRCT Score was 21/25 and the infection was severe. There was no any sign of oral candidiasis, subcutaneous emphysema, or tissue or organ damage or no any other abnormality was detected during Covid 19 tratment. No bacterial growth or fungal growth observed on investigation. After some days and treatment of covid 19 the patient was developed a Oral Candidiasis and Subcutaneous Emphysema and SARI. The working diagnosis was finalized by doctors i.e. Oral Candidiasis With Subcutaneaous Emphyema and SARI. After expert medical management and excellent nursing care patient was discharged with full recovery. Conclusion: In this study, we mainly focus on expert medical management and excellent nursing care helped in managing the complicated case very nicely. All the patient response was positive for conservative and nursing management and after treatment the patient was discharged without any complications and satisfaction with full recovery.

A 2 Years Child Bronchopneumonia with Down Syndrome

Introduction: Pneumonia and respiratory infections impact infants and children with Down syndrome; pneumonia is a leading cause of mortality in adults with Down syndrome. Case Presentation: A 2 years old child came to AVBRH hospital with a history of fever, cough and cold for 6 days. The patient was admitted to the pediatric ward for management. Suddenly patient started to breathlessness, increase in serum creatinine and acidotic breathing. The patient shifted to the pediatric intensive care unit. Intervention: The treatment of patients was started immediately after admission. The patient's condition was dull after the examination and patient condition inspection doctors decide to intubate the patient for further management and recovery of the patient. Conclusion: In this report, we mainly focus on expert medical management and excellent nursing care helped in managing the complicated case very nicely. The patient response was positive to conservative and nursing management. The patient was discharged without postoperative complications and satisfactory with recovery.

Predicting patient response with models trained on cell lines and patient-derived xenografts by nonlinear transfer learning

Preclinical models have been the workhorse of cancer research, producing massive amounts of drug response data. Unfortunately, translating response biomarkers derived from these datasets to human tumors has proven to be particularly challenging. To address this challenge, we developed TRANSACT, a computational framework that builds a consensus space to capture biological processes common to preclinical models and human tumors and exploits this space to construct drug response predictors that robustly transfer from preclinical models to human tumors. TRANSACT performs favorably compared to four competing approaches, including two deep learning approaches, on a set of 23 drug prediction challenges on The Cancer Genome Atlas and 226 metastatic tumors from the Hartwig Medical Foundation. We demonstrate that response predictions deliver a robust performance for a number of therapies of high clinical importance: platinum-based chemotherapies, gemcitabine, and paclitaxel. In contrast to other approaches, we demonstrate the interpretability of the TRANSACT predictors by correctly identifying known biomarkers of targeted therapies, and we propose potential mechanisms that mediate the resistance to two chemotherapeutic agents.

Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths worldwide. Sorafenib has been used as a first-line systemic treatment for over a decade. However, resistance to sorafenib limits patient response and presents a major hurdle during HCC treatment. Lenvatinib has been approved as a first-line systemic treatment for advanced HCC and is the first agent to achieve non-inferiority against sorafenib. Therefore, in the present study, we evaluated the inhibition efficacy of lenvatinib in sorafenib-resistant HCC cells. Only a few studies have been conducted on this topic. Two human HCC cell lines, Huh-7 and Hep-3B, were used to establish sorafenib resistance, and in vitro and in vivo studies were employed. Lenvatinib suppressed sorafenib-resistant HCC cell proliferation mainly by inducing G1 cell cycle arrest through ERK signaling. Hep-3B sorafenib-resistant cells showed partial cross-resistance to lenvatinib, possibly due to the contribution of poor autophagic responsiveness. Overall, the findings suggest that the underlying mechanism of lenvatinib in overcoming sorafenib resistance in HCC involves FGFR4-ERK signaling. Lenvatinib may be a suitable second-line therapy for unresectable HCC patients who have developed sorafenib resistance and express FGFR4.

Role of PET/CT in initial evaluation of lymphoma patients

Background Accurate radiologic assessment of treatment response in lymphoma patients is important to evaluate the effectiveness of treatment and consequently predict the relapse; the value of PET/CT for post-treatment prognosis prediction has been recently investigated. The aim of this study is to highlight the prognostic value of PET-CT metabolic volumetric parameters in the evaluation of lymphoma patients. Results Among the included 40 patients, post-treatment SUV, MTV, and TLG were significantly lower in a responsive group than the non-responsive group. % changes of all quantitative PET/CT parameters were significantly higher in the responsive group than the non-responsive group. Conclusions This study suggests that pre-treatment PET/CT quantitative measures (except baseline SUVmax) are not conclusive in the prediction of patient response to treatment; however, the ΔSUVmax, ΔMTV, and ΔTLG% from the baseline to the end of therapy could be used in predicting patient response to treatment, determining patient prognosis, and suggesting the relapse.