Single domain antibodies derived from ancient animals as broadly neutralizing agents for SARS-CoV-2 and other coronaviruses.

With severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as an emergent human virus since December 2019, the world population is susceptible to coronavirus disease 2019 (COVID-19). SARS-CoV-2 has higher transmissibility than the previous coronaviruses, associated by the ribonucleic acid (RNA) virus nature with high mutation rate, caused SARS-CoV-2 variants to arise while circulating worldwide. Neutralizing antibodies are identified as immediate and direct-acting therapeutic against COVID-19. Single-domain antibodies (sdAbs), as small biomolecules with non-complex structure and intrinsic stability, can acquire antigen-binding capabilities comparable to conventional antibodies, which serve as an attractive neutralizing solution. SARS-CoV-2 spike protein attaches to human angiotensin-converting enzyme 2 (ACE2) receptor on lung epithelial cells to initiate viral infection, serves as potential therapeutic target. sdAbs have shown broad neutralization towards SARS-CoV-2 with various mutations, effectively stop and prevent infection while efficiently block mutational escape. In addition, sdAbs can be developed into multivalent antibodies or inhaled biotherapeutics against COVID-19.

Thrombopoietin maintains cell numbers of hematopoietic stem and progenitor cells with megakaryopoietic potential.

Thrombopoietin (THPO) has long been known to influence megakaryopoiesis and hematopoietic stem and progenitor cells (HSPCs), though the exact mechanisms through which it acts are unknown. Here we show that MPL expression correlates with megakaryopoietic potential of HSPCs and identify a population of quiescent progenitor cells that show limited dependence on THPO signalling. We show that THPO is primarily responsible for maintenance of hematopoietic cells with megakaryocytic (Mk) differentiation potential and their subsequent Mk differentiation and maturation. The loss of Mks in THPO knockout (KO) mouse models results in a reduction of the Mk derived chemokine platelet factor 4 (CXCL4/PF4) in the bone marrow and administration of recombinant CXCL4/PF4 rescues the loss of progenitor cell quiescence observed in these mice. CXCL4/PF4 treatment does not rescue reduced HSPC numbers suggesting that thrombopoietin directly maintains HSPC numbers.

Modification of the bone marrow MSC population in a xenograft model of early multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy characterized by clonal proliferation of abnormal plasma cells. MM dysregulates the homeostasis of the bone niche cells like osteoclasts and osteoblasts, responsible for the bone maintenance leading to bone loss and hypercalcemia, as well as the normal immune cells leading to immunodeficiency and anemia. Osteoblasts are part of the cell population differentiating from mesenchymal stem cells (MSC). MSC also gives rise to other cell types such as adipocytes and chondrocytes. It has been observed that adipocytes support MM growth by increasing its survival and chemo-resistance. As adipocytes originate from MSC, the understanding of early modifications in the MSC population during the disease progression is of paramount importance and may help for early diagnosis of MM. Herein, we have evaluated the modification of the MSC population in the bone niche in an in vivo model of MM. Our results showed that before an observable engraftment of MM in the bone niche, the proportion of MSC population is significantly decreased, while a significant increase in adipocyte related genes such as PPARγ and CEBPα expression appears, with no difference in osteogenic differentiation. These results suggest that the bone niche is switching to a "fatty" marrow which would create an adequate microenvironment for MM. This led us to screen for and identify modulated adipokines in the sera of this in vivo MM-mice model. Such changes could reflect early signs of MM and potentially be exploited as detection biomarkers of the disease.

First Report on Stem Cell Transplant From Iraq.

The Iraqi Bone Marrow Transplantation Center is located in the medical city complex of Bab Almuadham in Baghdad, Iraq. It was established on March 11, 2002, and performed its first mini-allotransplant for acute myeloid leukemia on January 24, 2003. Among 16 patients who received hematopoietic stem cell transplant between January 2003 and January 2010, one patient underwent allogeneic bone marrow transplant for acute myeloid leukemia and 15 patients received autologous bone marrow transplant for the following indications: 5 had multiple myeloma, 9 had lymphoma (8 with Hodgkin disease and 1 with non- Hodgkin lymphoma), and 1 had rhabdomyosarcoma. Median age was 34 years (range, 10-56 y), and our patient group included 8 females and 8 males. Of the 16 patients, 12 are still alive. The mortality rate was 25% as measured during our follow-up from 2 to 96 months. Of the 9 patients with lymphoma, 1 died and 2 relapsed after transplant. Therefore, our survival rate in lymphoma was 88%, with progression-free survival in lymphoma ranging from 2 to 66 months (mean survival of 13 mo, mode of 13 mo). For the 5 patients with multiple myeloma who received transplants, 1 died and 2 relapsed, with effective-free survival of 6 to 13 months. Our results show that high-dose chemotherapy followed by autologous stem cell transplant can induce long-term disease control in this cohort of patients with refractory or advanced Hodgkin disease; progression-free survival for our cohort was 50%, with survival comparable to those reported in the literature.

Epithelial to mesenchymal transition (EMT) biomarkers--E-cadherin, beta-catenin, APC and Vimentin--in oral squamous cell carcinogenesis and transformation.

OBJECTIVES: To investigate immunohistochemical (IHC) analysis of E-cadherin, ß-catenin, APC and Vimentin for prediction of oral malignant transformation. MATERIALS AND METHODS: Immunoreactivity for E-cadherin, ß-catenin, APC and Vimentin were determined for 100 oral biopsies classified as normal, mild dysplasia, moderate-severe dysplasia or OSCC, using the IHC scoring or label index scoring systems. Co-expression of biomarkers and correlation with histopathological grading was analysed. Vimentin and E-cadherin results were confirmed by RT-PCR and further investigated in vitro using a novel organotypic cell invasion model based on human dermis. RESULTS: A trend for decreased E-cadherin expression but increased Vimentin expression that correlated with increased disease severity was observed. Epithelial ß-catenin localisation shifted from being membranous to cytoplasmic/nuclear with increased histopathological grade severity. Relative to normal, APC expression was decreased for mild dysplasia but increased for OSCC. Co-expression of ß-catenin, APC and Vimentin (Spearman rank correlation) suggests interdependence of these molecules and involvement of the Wnt pathway in oral malignant transformation. Relative mRNA expression of E-cadherin for dysplasia and OSCC were less than 1% of normal tissue values, and mRNA expression of Vimentin was 3.7 times higher for OSCC than normal. After 63 days of organotypic culture neoplastic oral keratinocytes (PE/CA-PJ15) lost expression of E-cadherin and gained expression of Vimentin relative to their non-invasive counterparts in the epithelium. CONCLUSIONS: Trends in the expression of EMT markers - E-cadherin, ß-catenin, APC and Vimentin - suggest their involvement in oral carcinogenesis via Wnt pathway dysregulation. Aberrant expression of ß-catenin, APC and Vimentin are potential markers of malignant transformation.

Clinical outcome of 50 progressive multiple sclerosis patients treated with cellular therapy in iraq.

BACKGROUND AND OBJECTIVES: Multiple Sclerosis is a disease characterized by multifocal areas of demyelination in the brain and spinal cord, with associated inflammatory cell infiltrates, reactive gliosis, and axonal degeneration. It typically presents in young adults with episodic neurologic dysfunction, our aim is to find new simple method to treat multiple sclerosis by hematopoietic stem cells derived from peripheral blood. METHODS AND RESULTS: 50 patients suffering from multiple sclerosis worsening despite pharmacological treatment were treated by means of several intrathecal injections of peripheral blood cells harvested by aphaeresis after G-CSF(granulocyte colony stimulating factor) treatment. 24 patients (48% ) had a reduction of EDSS score. 8 patients had a relapse, but it was milder than usual and more easily controlled by cortisone. CONCLUSIONS: Since mesenchymal cells increase in the peripheral blood after G-CSF stimulation, a peripheral blood harvest seems easier and cheaper than mesenchymal cells cultivation prior to the injection. It seems a reasonable treatment for progressive multiple sclerosis.

A prospective study on the pattern of medication use for schizophrenia in the outpatient pharmacy department, Hospital Tengku Ampuan Rahimah, Selangor, Malaysia.

Schizophrenia is a chronic psychiatric disorder and pharmacotherapy plays a major role in its management. The 1950s and early 1960s saw milestones in the introduction of psychotropic drugs in clinical practice. A review of drug prescriptions in different settings provides an insight into the pattern of drug use, identifies drug-related problems and may be used to compare recommended guidelines with actual practice. This effort led to the evaluation of the drug prescribing pattern of antipsychotics in patients attending the psychiatric clinic at a government hospital. The data from 371 antipsychotic medication prescriptions that included 200 prescriptions for schizophrenia were collected during one month (1rst-31rst August 2008) at the outpatient pharmacy department. The mean age of patients was 35.0 years (SD = 1.131), with a male to female ratio of 2:1. The most widely used oral antipsychotic was haloperidol (16.3%) while the most common depot preparation prescribed was zuclopenthixol decanoate (8.8%). The daily dose of the average antipsychotic prescribed in this clinic was 342.06 mg equivalent of chlorpromazine. There was no relation between the doses received and ethnicity of the patient (Malay, Chinese or Indian). However, there was a significant relationship between the prescribed dose and patient age (P < 0.042). Nearly 32% of the schizophrenia patients were prescribed with atypical antipsychotics such as olanzapine (10.8%), risperidone (10.0%), quetiapine (7.6%) and clozapine (3.2%). Monotherapy was given to 73.0% of the schizophrenia patients. The majority of patients also received antidepressants. To conclude, this study gave evidence that physicians had a strong preference for monotherapy with conventional antipsychotic drugs while the use of atypical drugs was less prevalent.

Roscovitine synergizes with conventional chemo-therapeutic drugs to induce efficient apoptosis of human colorectal cancer cells.

AIM: To examine the ability of cyclin-dependent kinase inhibitor (CDKI) roscovitine (Rosco) to enhance the antitumor effects of conventional chemotherapeutic agents acting by different mechanisms against human colorectal cancer. METHODS: Human colorectal cancer cells were treated, individually and in combination, with Rosco, taxol, 5-Fluorouracil (5-FU), doxorubicine or vinblastine. The antiproliferative effects and the type of interaction of Rosco with tested chemotherapeutic drugs were determined. Cell cycle alterations were investigated by fluorescence-activated cell sorter FACS analysis. Apoptosis was determined by DNA fragmentation assay. RESULTS: Rosco inhibited the proliferation of tumor cells in a time- and dose-dependent manner. The efficacies of all tested chemotherapeutic drugs were markedly enhanced 3.0-8.42 multiply 10(3) and 130-5.28 multiply 10(3) fold in combination with 5 and 10 microg/mL Rosco, respectively. The combination of Rosco and chemotherapeutic drugs inhibited the growth of human colorectal cancer cells in an additive or synergistic fashion, and in a time and dose dependent manner. Rosco induced apoptosis and synergized with tested chemotherapeutic drugs to induce efficient apoptosis in human colorectal cancer cells. Sequential, inverted sequential and simultaneous treatment of cancer cells with combinations of chemotherapeutic drugs and Rosco arrested the growth of human colorectal cancer cells at various phases of the cell cycle as follows: Taxol/Rosco (G2/M- and S-phases), 5-FU/Rosco (S-phase), Dox/Rosco (S-phase) and Vinb/Rosco (G2/M- and S-phases). CONCLUSION: Since the efficacy of many anticancer drugs depends on their ability to induce apoptotic cell death, modulation of this parameter by cell cycle inhibitors may provide a novel chemo-preventive and chemotherapeutic strategy for human colorectal cancer.

The effect of electrical stimulation on a normal skin blood flow in active young and older adults.

BACKGROUND: Electrical stimulation (ES) shows promising results in increasing healing of decubitus ulcers. Recent studies show that skin blood flows (SBFs) are enhanced if the subject is exposed to a warm environment during treatment. The purpose of this investigation was to determine if blood flow would increase with ES in a physically active older population without wounds in a warm environment. MATERIAL/METHODS: Twenty-two healthy physically active males were divided into a young group (YG) (N=15, age= 32.1+/-8.3 years) and an older group (OG) (N=8, age= 64.5+/-6.2 years). ES (30 Hz, pulse width 250 microsec and maximum current of 15 mA) was applied on the right thigh for 15 minutes with the subject in a thermoneutral (25+/-0.5 degrees C) and a warm (35+/-0.5 degrees C) environment on two days. Skin blood flow was monitored by Laser Doppler Imager. Tympanic temperature, sweat rates, and skin temperatures were monitored on the forehead, chest, and both thighs during the experiment to assess autonomic stress. RESULTS: The skin temperatures and sweat rates were significantly higher in the YG than OG in the warm environment, with no differences found in the thermoneutral environment. In the warm environment, the SBFs were significantly different between pre, during, and post ES in both groups, and no difference was found between the two groups in either environment. CONCLUSIONS: The environment temperatures modulate the SBF response to ES. Global heat improves the SBF response to ES in non wounded skin in active young and old groups.

Genome sequence based, comparative analysis of the fluorescent amplified fragment length polymorphisms (FAFLP) of tubercle bacilli from seals provides molecular evidence for a new species within the Mycobacterium tuberculosis complex.

Tuberculosis in seals is caused by a member of the Mycobacterium tuberculosis complex referred to as the 'seal bacillus'. Fluorescent amplified-fragment length polymorphism (FAFLP) analysis was applied to isolates from four Australian and six Argentinean seals and compared with FAFLP pattern for standard strains belonging to the M. tuberculosis complex. The FAFLP profiles derived from EcoRI/MseI restricted fragments of blind coded DNA samples differentiated the seal bacillus from other members of the M. tuberculosis complex. According to the phylogenetic analysis performed using FAFLP data, seal bacilli appear to have diverged significantly from other members of the M. tuberculosis complex. We describe the suitability of a panel of 19 highly polymorphic markers for rapid identification and comparative genomic analyses of the seal bacillus strains. It is likely that these bacilli got separated from the M. tuberculosis lineage as a result of different insertion deletion events occurring on a genome wide scale. Our analysis reveals that the seal bacillus and M. bovis are genetically related and therefore, might have originated from a common ancestor. Our data additionally support the hypothesis that seal bacillus occupies a unique taxonomic position within the M. tuberculosis complex.

Xanthogranulomatous pyelonephritis in childhood.

Two cases of xanthogranulomatous pyelonephritis are reported in Arabs. Reviewing the literature, these cases were similar to previously reported cases. Although there are no pathognomonic clinical features, this disease should be considered in the differential diagnosis of a renal mass.