Therapy with pembrolizumab in treatment-naïve patients with nonmetastatic,mismatch repair deficient colorectal cancer

Therapy with immune checkpoint inhibitors (ICI) is effective in patients with metastatic mismatch-repair deficient (dMMR) colorectal cancer (CRC); however, data on treatment with neoadjuvant ICI in patients with locally advanced CRC are limited. From March 2019 to June 2020, five Danish oncological centers treated 10 patients with a treatment-naïve dMMR CRC with preoperative pembrolizumab, 9 with a nonmetastatic, unresectable colon cancer and 1 with a locally advanced rectum cancer. All 10 patients were evaluated regularly at a multidisciplinary team (MDT) meeting, and they all had a radical resection after a median of 8 cycles (range 2-13) of pembrolizumab. A microscopic evaluation of the resected tumors revealed no remaining tumor cells in five patients, while five still had tumor cells present. The patients were given no additional therapy. No recurrences were reported after a median follow-up of 26 months (range 23-38.5 months). Biopsies from Danish patients with CRC are routinely screened for dMMR proteins. In 2017, data from the Danish Colorectal Cancer Group showed that 19% (565/3000) of the patients with colon cancer and 1.5% (19/1279) of those with rectum cancer had an dMMR tumor. Among the patients with MMR determination, 26% (99/384) patients had a T4 dMMR colon cancer; thus, the 10 patients treated with neoadjuvant pembrolizumab comprised about 9% of the patients with a T4 dMMR colon cancer (9/99) and 5% of patients with dMMR rectal cancer (1/19). Therapy with pembrolizumab was feasible and effective. Larger prospective trials are needed to confirm our findings.     

Aliskiren protects against myocardial ischaemia‐reperfusion injury via an endothelial nitric oxide synthase dependent manner

Aliskiren, a direct renin inhibitor, has shown potent ability to attenuate hypertension. Our previous research has found that aliskiren protected against myocardial ischaemia‐reperfusion (I/R) injury and enhanced phosphorylation of endothelial nitric oxide synthase (eNOS) in spontaneously hypertensive rats. However, whether the cardioprotective effect of aliskiren against myocardial I/R injury was eNOS‐dependent is unknown. In the present study, 12‐week‐old male eNOS knockout (eNOS^?/?) and wild‐type C57BL/6J mice (WT) were orally administrated with the dose of 50 mg/kg per day of aliskiren. After a 4‐week treatment, aliskiren decreased blood pressure in eNOS^?/? mice, and reduced renin‐angiotension II levels in both eNOS^?/? and WT mice. Aliskiren also improved left ventricular ejection fraction (EF) and fractional shortening (FS), decreased myocardial infarct size, reduced creatine kinase (CK) and lactate dehydrogenase (LDH) activity in plasma, attenuated dihydroethidium (DHE) fluorescence and levels of malondialdehyde (MDA), enhanced superoxide dismutase (SOD) activity and total antioxidant capacity (T‐AOC) in myocardium, increased SOD and thioredoxin (Trx) proteins expression in WT mice subjected to 30 minutes of ischaemia followed by reperfusion for 24 hours. However, aliskiren failed to restore all of the above indices in eNOS^?/? mice subjected to the same I/R injury. Our study indicated that aliskiren protected against myocardial I/R injury via an eNOS dependent manner.     

A Longitudinal Survey for Genome-based Identification of SARS-CoV-2 in Sewage Water in Selected Lockdown Areas of Lahore City,Pakistan: A Potential Approach for Future Smart Lockdown Strategy

In 2019, the newly emerged SARS-CoV-2 virus caused pneumonia-like illness. The disease rapidly spread globally, leading to a worldwide outbreak referred to as the COVID-19 pandemic. The affected patients show symptoms of fever, dry cough, respiratory distress, myalgia, and gastrointestinal disturbance. As of April 5, 2021, 132,083,022 people worldwide were affected by COVID-19, while 2,868,454 people died due to the disease[1]. SARS-CoV-2-positive patients may remain asymptomatic or start showing symptoms in 2?14 days after exposure to the virus[2]. The viral infection can be diagnosed from nasopharyngeal, throat, alveolar lavage, lacrimal, blood, and stool samples. The patient starts shedding the virus in stool regardless of being symptomatic or asymptomatic, which makes sewage-based detection of the virus to be more beneficial in the early infection stage.     

Managing the cervical spine in multiple myeloma patients

Discuss the relevant literature on surgical and nonsurgical treatments for multiple myeloma (MM) and their complementary effects on overall treatment. Existing surgical algorithms designed for neoplasia of the spine may not suit the management of spinal myeloma. Less than a fifth of metastatic, including myelomatous lesions, occur in the cervical spine but have a poorer prognosis and surgery in this area carries a higher morbidity. With the advances of chemotherapy, early access to radiotherapy, early orthosis management, and high definition imaging, including CT and MRI, surgical indications in MM have changed. Medical decompression (or oncolysis), including in the presence of neurological deficit and orthotic stabilization, are proving viable nonsurgical options to manage MM. A key to decision making is the assessment and monitoring of biomechanical spinal stability as part of a multidisciplinary approach.     

Prognostic Significance of Cyclin D1 Over-expression in Colorectal Cancer: An Experience from Madinah,Saudi Arabia

Background and study aim: Cyclin D1 is a key regulatory protein in the cell cycle and is over-expressed inmany tumors, including endometrial, thyroid, urothelial, breast, brain gliomas, and esophageal cancers. The mainaim of the present study is to examine the expression pattern of cyclin D1 and its correlation with the differentclinicopathological features in patients with colorectal camcer (CRC) from the Madinah region of Saudi Arabia.Patients and methods: The archival tumor blocks were analyzed using immunohistochemistry for Cyclin D1over-expression in 324 CRC patients diagnosed from January 2006 to December 2017, at the Department of Pathology,King Fahad Hospital, Madinah, Saudi Arabia. Results: Cyclin D1 over-expression was absent in normal mucosa, while15% cases of adenoma showed its over-expression. In CRC, Cyclin D1 was expressed at high levels in 24.1% of case.No significant correlation was observed between Cyclin D1 over-expression and age, gender, tumor size, type andlocation. However, Cyclin D1 over-expression exhibited a significant correlation with tumor differentiation (p=0.04),lymph node involvement (p=0.001), lymphovascular invasion (p=0.001), distant metastasis (p=0.006) and AJCC staging(p=0.001). The Kaplan-Meir analysis revealed a shorter period of survival with Cyclin D1 over-expression (p=0.000).The Cox-regression model analysis showed that Cyclin D1 over-expression was an independent prognostic markerin CRC (p=0.000). Conclusion: Cyclin D1 over-expression increases during normal-adenoma-carcinoma sequence.The significant association observed between Cyclin D1 over-expression, advanced tumor stage and short survivalperiod clearly suggest the role of Cyclin D1 in the carcinogenesis and progression of CRC.     

Rare β-Globin Gene Mutations in Pakistan

The aim of this study was to analyze the rare β-thalassemia (β-thal) mutations in the Pakistani population. A total of 8716 unrelated Pakistani individuals having children with transfusion-dependent thalassemia were investigated by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) for the previously reported common and rare β-thal mutations. Genomic sequencing of the β-globin gene and its immediate 5' and 3' flanking regions was done where no known mutation was found. Out of the 8716 individuals studied, 88 (1.0%) were not characterized by ARMS-PCR. Genomic sequencing revealed that 67 (0.82%) individuals had 19 different β-thal mutations including one novel mutation (HBB: c.136delT). The remaining 21 (0.26%) individuals did not show any mutation on the β-globin gene and its immediate flanking regions. The characterized alleles included seven (0.09%) in the 5' untranslated region (5'UTR), 29 (0.35%) in the coding regions, and 31 (0.38%) in the splice junction regions. HBB: c.92+1G>A and HBB: c.113G>A were the most frequently seen rare mutations. The spectrum of β-thal mutations in the Pakistani population is very diverse. In addition to the already reported mutations, another 19 different types of mutations were found. Interestingly, 21 individuals who had children with transfusion-dependent thalassemia and one known β-thal mutation, did not show any mutation on the β-globin gene. HBB: c.92+1G>A and HBB: c.113G>A are the most frequently seen rare mutations in Pakistan.     

In vivo brain microdialysis: advances in neuropsychopharmacology and drug discovery

INTRODUCTION: Microdialysis is an important in vivo sampling technique, useful in the assay of extracellular tissue fluid. The technique has both pre-clinical and clinical applications but is most widely used in neuroscience. The in vivo microdialysis technique allows measurement of neurotransmitters such as acetycholine (ACh), the biogenic amines including dopamine (DA), norepinephrine (NE) and serotonin (5-HT), amino acids such as glutamate (Glu) and gamma aminobutyric acid (GABA), as well as the metabolites of the aforementioned neurotransmitters, and neuropeptides in neuronal extracellular fluid in discrete brain regions of laboratory animals such as rodents and non-human primates. AREAS COVERED: In this review we present a brief overview of the principles and procedures related to in vivo microdialysis and detail the use of this technique in the pre-clinical measurement of drugs designed to be used in the treatment of chemical addiction, neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and as well as psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. This review offers insight into the tremendous utility and versatility of this technique in pursuing neuropharmacological investigations as well its significant potential in rational drug discovery. EXPERT OPINION: In vivo microdialysis is an extremely versatile technique, routinely used in the neuropharmacological investigation of drugs used for the treatment of neurological disorders. This technique has been a boon in the elucidation of the neurochemical profile and mechanism of action of several classes of drugs especially their effects on neurotransmitter systems. The exploitation and development of this technique for drug discovery in the near future will enable investigational new drug candidates to be rapidly moved into the clinical trial stages and to market thus providing new successful therapies for neurological diseases that are currently in demand.     

Autozygosity mapping of a large consanguineous Pakistani family reveals a novel non-syndromic autosomal recessive mental retardation locus on 11p15-tel

Autosomal recessive inherited mental retardation is an extremely heterogeneous disease and accounts for approximately 25% of all non-syndromic mental retardation cases. Autozygosity mapping of a large consanguineous Pakistani family revealed a novel locus for non-syndromic autosomal recessive mental retardation (NS-ARMR). The affected individuals showed low IQ and cognitive impairment without any neurological, skeletal, and biochemical abnormalities. All known NS-ARMR genes were excluded by STS markers, so autozygosity mapping by microarray single-nucleotide polymorphism (SNP) analysis were done in all sampled individuals in the family. The nuclear central loop in the five generation family showed homozygosity for a 6-Mb telomeric region on 11p15, whereas all other linkage regions were excluded by calculation of logarithm of odds (LOD) for the SNP microarray data. A maximum LOD score of Z = 3.31 was calculated for the mapped region. These results suggest a novel genetic locus, MRT17, for NS-ARMR.