The perception of genetic diseases and premarital screening tests in the central region of Saudi Arabia.

The prevalence of consanguineous marriages (CMs) varies worldwide from one country to another. However, the Middle East stands out as a region with a notably high rate of CMs. CM is particularly widespread in Saudi Arabia, where the prevalence of autosomal recessive genetic diseases has increased. This study aims to identify the Saudi population's awareness of genetic diseases and premarital screening tests (PMSTs). It also seeks to understand couples' perceptions of genetic diseases before and after marriage and their attitudes towards PMSTs and genetic counselling (GC) in reducing the risk of CM. Through the administration of online questionnaires, this cross-sectional study surveyed 2,057 participants to assess their awareness of genetic diseases and their understanding of testing and preventive measures for inherited diseases. Descriptive analysis, nonparametric chi-square tests and logistic regressions were performed to assess the association of categorical responses. This study included 2,035 Saudi Arabian respondents. A significant correlation was found between positive family history and partner selection (p = 0.001), as well as between partnering within the same tribe (p = 0.000139), with a different tribe (p = 0.000138) and from another family (p = 0.000489). About 91.3% of participants expressed agreement regarding the need to enhance public awareness and knowledge concerning genetic disorders, while 87% agreed that increased government regulations are required to prevent the spread of genetic diseases in affected families. Despite increased awareness of genetic diseases and PMSTs, there appears to be a lack of understanding regarding the limitations of PMSTs. The persistently high rate of CM underscores the challenge of altering marriage customs. Further governmental efforts are required to promote awareness of alternative reproductive options, establish new regulations and expand screening programmes.

Dual synergistic inhibition of COX and LOX by potential chemicals from Indian daily spices investigated through detailed computational studies.

Cyclooxygenase (COX) and Lipoxygenase (LOX) are essential enzymes for arachidonic acid (AA) to eicosanoids conversion. These AA-derived eicosanoids are essential for initiating immunological responses, causing inflammation, and resolving inflammation. Dual COX/5-LOX inhibitors are believed to be promising novel anti-inflammatory agents. They inhibit the synthesis of prostaglandins (PGs) and leukotrienes (LTs), but have no effect on lipoxin formation. This mechanism of combined inhibition circumvents certain limitations for selective COX-2 inhibitors and spares the gastrointestinal mucosa. Natural products, i.e. spice chemicals and herbs, offer an excellent opportunity for drug discovery. They have proven anti-inflammatory properties. However, the potential of a molecule to be a lead/ drug candidate can be much more enhanced if it has the property of inhibition in a dual mechanism. Synergistic activity is always a better option than the molecule's normal biological activity. Herein, we have explored the dual COX/5-LOX inhibition property of the three major potent phytoconsituents (curcumin, capsaicin, and gingerol) from Indian spices using in silico tools and biophysical techniques in a quest to identify their probable inhibitory role as anti-inflammatory agents. Results revealed the dual COX/5-LOX inhibitory potential of curcumin. Gingerol and capsaicin also revealed favorable results as dual COX/5-LOX inhibitors. Our results are substantiated by target similarity studies, molecular docking, molecular dynamics, energy calculations, DFT, and QSAR studies. In experimental inhibitory (in vitro) studies, curcumin exhibited the best dual inhibitory activities against COX-1/2 and 5-LOX enzymes. Capsaicin and gingerol also showed inhibitory potential against both COX and LOX enzymes. In view of the anti-inflammatory potential these spice chemicals, this research could pave the way for more scientific exploration in this area for drug discovery.

Characterization of the binding of MRTX1133 as an avenue for the discovery of potential KRASG12D inhibitors for cancer therapy.

The Kirsten rat sarcoma (KRAS) oncoprotein has been on drug hunters list for decades now. Initially considered undruggable, recent advances have successfully broken the jinx through covalent inhibition that exploits the mutated cys12 in the switch II binding pocket (KRASG12C). Though this approach has achieved some level of success, patients with mutations other than cys12 are still uncatered for. KRASG12D is the most frequent KRAS mutated oncoprotein. It is only until recently, MRTX1133 has been discovered as a potential inhibitor of KRASG12D. This study seeks to unravel the structural binding mechanism of MRTX1133 as well as identify potential drug leads of KRASG12D based on structural binding characteristics of MRTX1133. It was revealed that MRTX1133 binding stabilizes the binding site by increasing the hydrophobicity which resultantly induced positive correlated movements of switches I and II which could disrupt their interaction with effector and regulatory proteins. Furthermore, MRTX1133 interacted with critical residues; Asp69 (- 4.54 kcal/mol), His95 (- 3.65 kcal/mol), Met72 (- 2.27 kcal/mol), Thr58 (- 2.23 kcal/mol), Gln99 (- 2.03 kcal/mol), Arg68 (- 1.67 kcal/mol), Tyr96 (- 1.59 kcal/mol), Tyr64 (- 1.34 kcal/mol), Gly60 (- 1.25 kcal/mol), Asp12 (- 1.04 kcal/mol), and Val9 (- 1.03 kcal/mol) that contributed significantly to the total free binding energy of - 73.23 kcal/mol. Pharmacophore-based virtual screening based on the structural binding mechanisms of MRTX1133 identified ZINC78453217, ZINC70875226 and ZINC64890902 as potential KRASG12D inhibitors. Further, structural optimisations and biochemical testing of these compounds would assist in the discovery of effective KRASG12D inhibitors.

Cancer of Unknown Primary Site: Real Entity or Misdiagnosed Disease?

Metastasis is a late event in the progression of any tumour. However, invasive cancers are occasionally detected in the form of metastatic lesions without a clearly detectable primary tumour. Cancer of unknown primary site (CUP) is defined as a confirmed metastatic tumour, with unknown primary tumour site, despite the standardized diagnostic approach that includes clinical history, routine laboratory tests, and complete physical examination. Due to the lack of basic research on its primary causes, CUP is appropriately termed an 'orphan' cancer. Nevertheless, CUP accounts for 2-5% of diagnosed malignancies. To date, it is unclear whether CUP is an entity with primary dormancy as its hallmark or an entity with genetic abnormalities that cause it to manifest as a primary metastatic disease. In this review, we discuss different aspects of CUP, including its current diagnostic methods, angiogenesis effectors, relationship with cancer stem cells and current treatments.