Early increase of plasma soluble VEGFR-2 is associated with clinical benefit from second-line treatment of paclitaxel and ramucirumab in advanced gastric cancer

Ramucirumab plus paclitaxel is considered the standard of care in the second-line treatment of gastric carcinoma (GC). The aim of this study was to evaluate plasma vascular endothelial growth factor-A (VEGF-A), VEGF-D, and circulating soluble VEGF receptor-2 (sVEGFR-2) as possible markers of resistance or response to ramucirumab administered with paclitaxel in pretreated metastatic GC patients. Plasma samples were collected at different time points (on days 1 and 15 of the first 3 cycles, at best radiologic response and at disease progression). VEGF-A, VEGF-D and sVEGFR-2 were analysed by ELISA. Correlations of biomarker baseline levels or dynamic changes with outcome measures were assessed. Progression-free survival (PFS) was the primary endpoint of the study. Forty-one patients were enrolled. VEGF-A and VEGF-D, but not sVEGFR-2, values significantly increased during treatment compared to baseline (P < 0.001). A positive correlation between VEGF-A and sVEGFR-2 at cycle 2 was found (P=0.045). At univariate analysis, higher baseline levels of VEGF-A were associated with worse OS (P=0.015). Early increase of sVEGFR-2 levels after the first treatment cycle was the only factor associated with longer PFS (6.6 vs. 3.6 months, P=0.049) and OS (18.6 vs. 5.2 months, P=0.008). Significance of sVEGFR-2 early increase was retained at multivariate analysis for OS (HR 0.32; 95% CI 0.12-0.91; P=0.032). The reported results confirmed the prognostic role of baseline VEGF-A and, with the limitations of the limited sample size and the lack of a control arm, suggested that the early increase of sVEGFR-2 after 1 cycle of treatment could be a potential predictive biomarker of benefit from second-line ramucirumab plus paclitaxel in GC.     

Understanding the Driving Forces That Trigger Mutations in SARS-CoV-2: Mutational Energetics and the Role of Arginine Blockers in COVID-19 Therapy

SARS-CoV-2 is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. Because the molecular biology of this virus has been studied in such great detail, it represents an archetypal paradigm for research into new antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis of furin and 3CLpro cleavage sites that augment infection. Non-RBD and non-interfacial mutations assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Kappa, Lambda and Omicron variants, which stabilize the RBD-ACE2 complex, are investigated by free-energy computational approaches, as well as equilibrium and steered molecular dynamic simulations. Considered also are the structural hydropathy traits of the residues in the interface between SARS-CoV-2 RBD and ACE2 protein. Salt bridges and π-π interactions are critical forces that create stronger complexes between the RBD and ACE2. The trend of mutations is the replacement of non-polar hydrophobic interactions with polar hydrophilic interactions, which enhance binding of RBD with ACE2. However, this is not always the case, as conformational landscapes also contribute to a stronger binding. Arginine, the most polar and hydrophilic among the natural amino acids, is the most aggressive mutant amino acid for stronger binding. Arginine blockers, such as traditional sartans that bear anionic tetrazoles and carboxylates, may be ideal candidate drugs for retarding viral infection by weakening S-protein RBD binding to ACE2 and discouraging hydrolysis of cleavage sites. Based on our computational results it is suggested that a new generation of “supersartans”, called “bisartans”, bearing two anionic biphenyl-tetrazole pharmacophores, are superior to carboxylates in terms of their interactions with viral targets, suggesting their potential as drugs in the treatment of COVID-19. In Brief: This in silico study reviews our understanding of molecular driving forces that trigger mutations in the SARS-CoV-2 virus. It also reports further studies on a new class of “supersartans” referred to herein as “bisartans”, bearing two anionic biphenyltetrazole moieties that show potential in models for blocking critical amino acids of mutants, such as arginine, in the Delta variant. Bisartans may also act at other targets essential for viral infection and replication (i.e., ACE2, furin cleavage site and 3CLpro), rendering them potential new drugs for additional experimentation and translation to human clinical trials.     

Midbrain syndrome with eye movement disorder: dramatic improvement after cranioplasty

BACKGROUND Patients with skull defects sometimes develop neurological deficits, which have been grouped under “the syndrome of the trephined”. The deficits are usually nonspecific or nonlocalizing, such as apathy or diffuse headaches. We report, to our knowledge, a first case of severe midbrain syndrome associated with a skull defect. Cranioplasty dramatically resolved the patient's symptoms. A midbrain syndrome represents the main manifestation of the syndrome of the trephined and can be corrected by cranioplasty. CLINICAL PRESENTATION A 38-year-old man with head trauma and epidural hematoma initially had normal eye motility. He developed a skull defect after infection following cranioplasty. He presented with onset of neurological symptoms one year after head trauma with a skull defect, a small divergent and vertical strabismus, elevation deficit of both eyes, headaches and fatigue. Over several months he developed severe bilateral deficit of adduction, elevation, depression and convergence. He had neuropsychological deficits, fatigue, headaches and impaired coordination. Neuroimaging and lumbar puncture did not show evidence of increased intracranial pressure or hydrocephalus. INTERVENTION Cranioplasty using Palacos was performed one-and-a-half years after trauma. Immediately after surgery, the patient noted remarkable improvement in his symptoms. Headaches and fatigue disappeared within two days. Two weeks after cranioplasty the patient had orthotropia and virtually normal ocular motility. Neurological symptoms completely disappeared. Recovery remained sustained for over 5 years after cranioplasty. CONCLUSION To our knowledge, this represents the first case of the syndrome of the trephined in which the neurological deficits map primarily to the brainstem and show rapid improvement following cranioplasty. We show that cranioplasty in patients with large skull defects is indicated for more then cosmetic reasons and should be considered even after longer periods following a trauma.     

Involvement of microRNAs in breast cancer

MicroRNAs regulate numerous aspects of normal and pathologic cellular processes, including cancer. Breast cancer is a heterogeneous form of cancer that is derived from mammary epithelial cells. This review discusses the involvement of microRNAs in the regulation of normal mammary epithelial stem cells, their differentiation into basal and luminal phenotypes, and their control of breast cancer stem cells, also referred to as tumor-initiating cells. In the second section, we summarize the findings of differential microRNA expression in normal versus breast tumor tissue and among the various subtypes of breast cancer (primarily luminal, basal-like, and HER2). In the third and fourth sections of the review, specific mRNA targets of microRNAs in breast cancer are discussed, including those encoding the estrogen receptor-alpha and epidermal growth factor receptor, as well as survival, tumor suppressor, and cell-cycle-related proteins. Finally, the involvement of microRNAs in the promotion and suppression of breast cancer metastasis is reviewed. The studies presented herein provide a rationale for the design of therapeutic agents that target specific microRNAs in the treatment of breast cancer. Hopefully, this review will provide an impetus for more studies on the role of microRNAs in the regulation of normal mammary gland development and function.     

The in vivo effects of Tulbhagia violacea on blood pressure in a salt-sensitive rat model

Aim of the study

The in vivo effects of Tulbhagia violacea on systemic arterial blood pressure and on the renin-angiotensin system in a Dahl salt-sensitive rat model were investigated.

Materials and methods

Animals were treated for 14 days intraperitoneally as follows: Tulbhagia violacea (Tvl) (50 mg/kg b.w.), captopril (Cap) (10 mg/kg b.w.) or DMSO (Con). Baseline blood pressures were recorded prior to the commencement of the study and biweekly during the experimental period. Urine volume and sodium concentration were measured during the experimental period. On day 15, animals were anaesthetized (sodium thiopentane, 50 mg/kg, i.p.), blood samples for aldosterone levels were taken and the kidneys removed for determining AT1a mRNA expression.

Results

Cap and Tvl groups showed significantly reduced AT1a mRNA expressions by 3.11- and 5.03-fold, respectively, when compared to the Con group (p < 0.05). When compared to baseline blood pressures (day 0); Cap and Tvl showed reductions in systolic blood pressure (SBP) of 7.76 ± 0.41% and 9.12 ± 0.31%, respectively (mean% decrease from day 0 to day 14). In contrast, in the Con group the systolic blood pressure increased from day 0 to day 14 by 4.66 ± 0.56%. Blood pressure changes in all treated groups differed from Con significantly. Systolic blood pressure decreased with the decrease in AT1a mRNA expressions in these groups. When comparing day 0 to day 14, urine output increased in the Cap and Tvl groups. In the Con group, urinary volume was reduced by day 14 as compared to day 0. Urinary sodium excretion was increased in the treated groups by day 14.

Conclusion

It can be concluded that Tulbhagia violacea reduces systemic arterial blood pressure in the Dahl rat by decreasing renal AT1 receptor gene expression and hence modulating sodium and water homeostasis.     

Obstetric gel shortens second stage of labor and prevents perineal trauma in nulliparous women: a randomized controlled trial on labor facilitation

OBJECTIVE: To determine whether the obstetric gel shortens the second stage of labor and exerts a protective effect on the perineum. METHOD: A total of 251 nulliparous women with singleton low-risk pregnancies in vertex position at term were recruited. A total of 228 eligible women were randomly assigned to Group A, without obstetric gel use, or to Group B, obstetric gel use, i.e., intermittent application into the birth canal during vaginal examinations, starting at the early first stage of labor (prior to 4 cm dilation) and ending with delivery. RESULTS: A total of 183 cases were analyzed. For vaginal deliveries without interventions, such as C-section, vaginal operative procedure or Kristeller maneuver, obstetric gel use significantly shortened the second stage of labor by 26 min (30%) (P=0.026), and significantly reduced perineal tears (P=0.024). First stage of labor and total labor duration were also shortened, but not significantly. Results did not show a significant change in secondary outcome parameters, such as intervention rates or maternal and newborn outcomes. No side effects were observed with obstetric gel use. CONCLUSION: Systematic vaginal application of obstetric gel showed a significant reduction in the second stage of labor and a significant increase in perineal integrity. Future studies should further investigate the effect on intervention rates and maternal and neonatal outcome parameters.     

Fetal facial profile in Pallister-Killian syndrome

Pallister-Killian syndrome (PKS) is a sporadic chromosomal anomaly, caused by a tissue-specific mosaic distribution of an additional isochromosome 12p. About 60 cases of prenatal diagnosis of PKS have been reported. Only 1 case of PKS is described on the basis of prenatal screening, presenting increased nuchal translucency. An abnormal fetal facial profile is described prenatally as sonographic evidence of PKS. We report a case of prenatal diagnosis in a fetus undergoing second-level scan due to positive triple screen with ultrasound features of PKS.