What is the best drug to treat COVID-19? The need for randomized controlled trials

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the biggest public health challenge to the biomedical community of the last century. Despite multiple public health measures,1, 2, 3 there remains an urgent need for pharmacologic therapies to treat infected patients, minimize mortality, and decrease pressures on intensive care units and health systems and optimally, they should also decrease subsequent transmission

Nivolumab-induced fulminant diabetic ketoacidosis followed by thyroiditis

Five days following the 3rd cycle of nivolumab, a monoclonal antibody, which acts as immune checkpoint inhibitor against the programmed cell death protein-1, for metastatic lung adenocarcinoma, a 56-year-old woman presented at the hospital critically ill. On admission, she had severe diabetic ketoacidosis (DKA), as evidenced by venous glucose of 47 mmol/L, blood ketones of 7.5 mmol/L, pH of 6.95 and bicarbonate of 6.6 mmol/L. She has had no personal or family history of diabetes mellitus (DM), while random venous glucose, measured 1 week prior to hospitalisation, was 6.1 mmol/L. On admission, her HbA1c was 8.2% and anti-GAD antibodies were 12 kIU/L (0–5 kU/L), while islet cell antibodies and serum C-peptide were undetectable. Nivolumab was recommenced without the development of other immune-mediated phenomena until 6 months later, when she developed hypothyroidism with TSH 18 U/L and low free T4. She remains insulin dependent and has required levothyroxine replacement, while she has maintained good radiological and clinical response to immunotherapy. This case is notable for the rapidity of onset and profound nature of DKA at presentation, which occurred two months following commencement of immunotherapy. Despite the association of nivolumab with immune-mediated endocrinopathies, only a very small number of patients developing type 1 DM has been reported to date. Patients should be closely monitored for hyperglycaemia and thyroid dysfunction prior to and periodically during immunotherapy

A real-world disproportionality analysis of FDA Adverse Event Reporting System (FAERS) events for baricitinib.

BACKGROUND: Baricitinib is approved for the treatment of rheumatoid arthritis (RA). The authors retrospectively investigated adverse events (AEs) by data-mining a self-reporting database to better understand toxicities, especially since it has been used during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A reporting odds ratio (ROR) was used to detect the risk signals from the data in the US Food and Drug Administration (FDA) adverse event reporting system database (FAERS). The definition relied on system organ class (SOCs) and preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA). RESULTS: The search retrieved 1,598 baricitinib-associated cases within the reporting period: 86 PTs with significant disproportionality were retained. Infections including 'herpes zoster,' 'oral herpes,' and 'herpes virus infection' were found at a similar rate to those reported in trials, and such events were rare. Reports emerged for several thrombotic adverse events, while these events were also rare. Unexpected safety signals as opportunistic infections were detected. Serious outcomes as death and life-threatening outcomes accounted for 9.76% of the reported cases. CONCLUSIONS: The incidence of these AEs does not appear above the background expected. These data are consistent with routine clinical observations and suggest the importance of pharmacovigilance

Sports balls as potential SARS-CoV-2 transmission vectors.

Objects passed from one player to another have not been assessed for their ability to transmit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We found that the surface of sport balls, notably a football, tennis ball, golf ball, and cricket ball could not harbour inactivated virus when it was swabbed onto the surface, even for 30 ​s. However, when high concentrations of 5000 ​dC/mL and 10,000 ​dC/mL are directly pipetted onto the balls, it could be detected after for short time periods. Sports objects can only harbour inactivated SARS-CoV-2 under specific, directly transferred conditions, but wiping with a dry tissue or moist 'baby wipe' or dropping and rolling the balls removes all detectable viral traces. This has helpful implications to sporting events

Resistin, an adipokine with non-generalized actions on sympathetic nerve activity

The World Health Organization has called obesity a global epidemic. There is a strong association between body weight gain and blood pressure. A major determinant of blood pressure is the level of activity in sympathetic nerves innervating cardiovascular organs. A characteristic of obesity, in both humans and in animal models, is an increase in sympathetic nerve activity to the skeletal muscle vasculature and to the kidneys. Obesity is now recognized as a chronic, low level inflammatory condition, and pro-inflammatory cytokines are elevated including those produced by adipose tissue. The most well-known adipokine released from fat tissue is leptin. The adipokine, resistin, is also released from adipose tissue. Resistin can act in the central nervous system to influence the sympathetic nerve activity. Here, we review the effects of resistin on sympathetic nerve activity and compare them with leptin. We build an argument that resistin and leptin may have complex interactions. Firstly, they may augment each other as both are excitatory on sympathetic nerves innervating cardiovascular organs; In contrast, they could antagonize each other's actions on brown adipose tissue, a key metabolic organ. These interactions may be important in conditions in which leptin and resistin are elevated, such as in obesity

Point-of-care SARS-CoV-2 serological assays for enhanced case finding in a UK inpatient population.

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Case identification is currently made by real-time polymerase chain reaction (PCR) during the acute phase and largely restricted to healthcare laboratories. Serological assays are emerging but independent validation is urgently required to assess their utility. We evaluated five different point-of-care (POC) SARS-CoV-2 antibody test kits against PCR, finding concordance across the assays (n=15). We subsequently tested 200 patients using the OrientGene COVID-19 IgG/IgM Rapid Test Cassette and find a sensitivity of 74% in the early infection period (day 5-9 post symptom onset), with 100% sensitivity not seen until day 13, demonstrating inferiority to PCR testing in the infectious period. Negative rate was 96%, but in validating the serological tests uncovered potential false-negatives from PCR testing late-presenting cases. A positive predictive value (PPV) of 37% in the general population precludes any use for general screening. Where a case definition is applied however, the PPV is substantially improved (95·4%), supporting use of serology testing in carefully targeted, high-risk populations. Larger studies in specific patient cohorts, including those with mild infection are urgently required to inform on the applicability of POC serological assays to help control the spread of SARS-CoV-2 and improve case finding of patients that may experience late complications

Efficacy and safety of first-line treatment strategies for anaplastic lymphoma kinase-positive non-small cell lung cancer: a Bayesian network meta-analysis.

Background: Targeted therapies have led to significant improvement in the management and prognosis of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). We performed a network meta-analysis of frontline treatment options of ALK-positive NSCLC to provide clinical guidance. Methods: PubMed, Embase, ClinicalTrials.gov, and international conference databases were searched to identify relevant trials from inception to June 30, 2021. Phase III randomized controlled trials (RCTs) comparing treatments for patients with ALK-positive advanced NSCLC in the first-line setting were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcomes: progression-free survival (PFS), overall survival (OS), risk of the central nervous system (CNS) progression, adverse events (AEs) of grade (G) 3 or higher (G3 AEs), or serious AEs (SAEs). Hazard ratios (HRs) and CI for primary outcome of PFS and secondary outcome of OS and risk of CNS progression were obtained. A multivariate, consistency model, fixed-effects analysis was used in the network meta-analysis. Data on G3 AEs and SAEs were abstracted and meta-analyzed. Risk of bias (RoB) was assessed using the Cochrane Collaboration's tool. Results: Nine RCTs comprising 2,484 patients were included with seven treatments: alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Compared with chemotherapy, ALK-tyrosine kinase inhibitors (TKIs) significantly prolong PFS and reduced risk of CNS progression except for ceritinib. Lorlatinib appears superior at reducing risk of CNS progression. None of the ALK-TKIs have a significantly prolonged OS as compared with chemotherapy. Lorlatinib increases the risk of G3 AEs as compared with alectinib (odds ratio 4.26 [95% CrI 1.22 to 15.53]), while alectinib caused the fewest G3 AEs. Conclusions: Lorlatinib is associated with the highest PFS benefit and lowest risk of CNS progression benefits for patients with advanced ALK-positive NSCLC, compared with other first-line treatments, but with higher toxicity. The implementation of a newer generation of ALK-TKIs in the first-line treatment of ALK-positive NSCLC into current clinical practice is evolving rapidly

Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer

Kinase suppressor of Ras 1 (KSR1) has been implicated in tumorigenesis in multiple cancers, including skin, pancreatic and lung carcinomas. However, our recent study revealed a role of KSR1 as a tumour suppressor in breast cancer, the expression of which is potentially correlated with chemotherapy response. Here, we aimed to further elucidate the KSR1-regulated signalling in response to genotoxic agents in breast cancer. Stable isotope labelling by amino acids in cell culture (SILAC) coupled to high-resolution mass spectrometry (MS) was implemented to globally characterise cellular protein levels induced by KSR1 in the presence of doxorubicin or etoposide. The acquired proteomic signature was compared and GO-STRING analysis was subsequently performed to illustrate the activated functional signalling networks. Furthermore, the clinical associations of KSR1 with identified targets and their relevance in chemotherapy response were examined in breast cancer patients. We reveal a comprehensive repertoire of thousands of proteins identified in each dataset and compare the unique proteomic profiles as well as functional connections modulated by KSR1 after doxorubicin (Doxo-KSR1) or etoposide (Etop-KSR1) stimulus. From the up-regulated top hits, several proteins, including STAT1, ISG15 and TAP1 are also found to be positively associated with KSR1 expression in patient samples. Moreover, high KSR1 expression, as well as high abundance of these proteins, is correlated with better survival in breast cancer patients who underwent chemotherapy. In aggregate, our data exemplify a broad functional network conferred by KSR1 with genotoxic agents and highlight its implication in predicting chemotherapy response in breast cancer

The tumor suppressor protein OPCML potentiates anti-EGFR and anti-HER2 targeted therapy in HER2-positive ovarian and breast cancer.

OPCML is a tumor suppressor gene that is frequently inactivated in ovarian cancer and many other cancers by somatic methylation. We have previously shown that OPCML exerts its suppressor function by negatively regulating a spectrum of receptor tyrosine kinases (RTKs), such as ErbB2/HER2, FGFR1 and EphA2, thus attenuating their related downstream signaling. The physical interaction of OPCML with this defined group of RTKs is a prerequisite for their downregulation. Overexpression/gene amplification of EGFR and HER2 is a frequent event in multiple cancers including ovarian and breast cancers. Molecular therapeutics against EGFR/HER2 or EGFR only, such as lapatinib and erlotinib respectively, were developed to target these receptors but resistance often occurs in relapsing cancers. Here we show that, though OPCML interacts only with HER2 and not with EGFR, the interaction of OPCML with HER2 disrupts the formation of the HER2-EGFR heterodimer and this translates into a better response to both lapatinib and erlotinib in HER2-expressing ovarian and breast cancer cell lines. Also, we show that high OPCML expression is associated with better response to lapatinib therapy in breast cancer patients and better survival in HER2-overexpressing ovarian cancer patients, suggesting that OPCML co-therapy could be a valuable sensitizing approach to RTK inhibitors