Interprofessional collaborative practice in health and social care for people living with multimorbidity: a scoping review protocol.

Background: Multimorbidity, the co-existence of two or more conditions within an individual at any one time, is globally increasing and forecasted to rise. This poses a significant challenge for current models of healthcare delivery, which are now ill-equipped to meet the future population health needs. Interprofessional collaborative practice is a specific way professionals work closely together and with patients and their families to improve patient outcomes.

People Living With HIV Have More Intact HIV DNA in Circulating CD4+ T Cells if They Have History of Pulmonary Tuberculosis.

Background: A primary barrier to curing HIV is the HIV reservoir. The leading infectious cause of death worldwide for people living with HIV is tuberculosis (TB), but we do not know how TB impacts the HIV reservoir.

Methods: Participants in identification and validation cohorts were selected from previously enrolled studies at Groupe Haïtien d'Étude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) in Port au Prince, Haiti.

Research priorities for progressive pulmonary fibrosis in the UK.

Introduction: Health research bodies recommend patient involvement and engagement in research and healthcare planning, although their implementation is not yet widespread. This deficiency extends to progressive pulmonary fibrosis (PPF), where crucial aspects remain unknown, including causal mechanisms, curative treatments and optimal symptom management. This study addresses these gaps by seeking stakeholders' perspectives to guide research and treatment directions.

Clinical and Demographic Factors Associated With Kaposi Sarcoma-Associated Herpesvirus Shedding in Saliva or Cervical Secretions in a Cohort of Tanzanian Women.

Background: Reasons for the high prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) in sub-Saharan Africa, and risk factors leading to viral reactivation and shedding, remain largely undefined. Preliminary studies have suggested that schistosome infection, which has been associated with impaired viral control, is associated with KSHV. In this study we sought to determine the relationship between active or infection and KSHV shedding.

Circulating CD4+ T cells in people with HIV and history of pulmonary tuberculosis have more intact HIV DNA.

Background: The primary barrier to curing HIV infection is the pool of intact HIV proviruses integrated into host cell DNA throughout the bodies of people living with HIV (PLHIV), called the HIV reservoir. Reservoir size is impacted by the duration of HIV infection, delay in starting antiretroviral therapy (ART), and breakthrough viremia during ART. The leading infectious cause of death worldwide for PLHIV is TB, but we don't know how TB impacts the HIV reservoir.

Infection Is Associated With Increased Monocytes and Fewer Natural Killer T Cells in the Female Genital Tract.

infection may impair genital mucosal antiviral immunity, but immune cell populations have not been well characterized. We characterized mononuclear cells from cervical brushings of women with and without infection. We observed lower frequencies of natural killer T cells and higher frequencies of CD14 monocytes in infected women.

Tetrathiomolybdate (TM)-associated copper depletion influences collagen remodeling and immune response in the pre-metastatic niche of breast cancer.

Tetrathiomolybdate (TM) is a novel, copper-depleting compound associated with promising survival in a phase II study of patients with high-risk and triple-negative breast cancer. We sought to elucidate the mechanism of TM by exploring its effects on collagen processing and immune function in the tumor microenvironment (TME). Using an exploratory cohort, we identified markers of collagen processing (LOXL2, PRO-C3, C6M, and C1M) that differed between those with breast cancer versus controls.

Influencing the Tumor Microenvironment: A Phase II Study of Copper Depletion Using Tetrathiomolybdate in Patients with Breast Cancer at High Risk for Recurrence and in Preclinical Models of Lung Metastases.

Purpose: Bone marrow-derived progenitor cells, including VEGFR2 endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models.

Pro1170 Ala polymorphism in HER2-neu is associated with risk of trastuzumab cardiotoxicity.

Background: Variations in single nucleotide polymorphisms (SNPs) have been associated with enhanced drug efficacy and toxicity in cancer therapy. SNP variations in the ErbB2 gene have been identified that alter the protein sequence of the HER2-neu protein, but how these polymorphisms affect prognosis and response to HER2 targeted therapy is unknown. We examined eleven ErbB2 SNPs that alter the HER2-neu amino acid sequence to determine whether any of these particular polymorphisms were associated with increased trastuzumab cardiotoxicity in a case-control study.

Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients.

Background: We sought to define the clinical and ultrastructure effects of ixabepilone (Ix), a microtubule-stabilizing chemotherapy agent on cutaneous sensory nerves and to investigate a potential mitochondrial toxicity mechanism.

Methods: Ten breast cancer patients receiving Ix underwent total neuropathy score clinical (TNSc) assessment, distal leg skin biopsies at cycle (Cy) 3 (80-90 mg/m(2)), Cy5 (160-190 mg/m(2)), and Cy7 (>200 mg/m(2)) and were compared to 5 controls. Skin blocks were processed for EM and ultrastructural morphometry of Remak axons done.

Phase II trial of bortezomib alone or in combination with irinotecan in patients with adenocarcinoma of the gastroesophageal junction or stomach.

Purpose: To determine the effectiveness of bortezomib plus irinotecan and bortezomib alone in patients with advanced gastroesophageal junction (GEJ) and gastric adenocarcinoma. We also sought to explore the effect of these therapeutics on tumor and normal gene expression in vivo.

Methods: Forty-one patients with advanced GEJ (89 %) or gastric (11 %) adenocarcinoma received bortezomib (1.

Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization.

Purpose: This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction.

Experimental Design: Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide.

Incremental increase in VEGFR1⁺ hematopoietic progenitor cells and VEGFR2⁺ endothelial progenitor cells predicts relapse and lack of tumor response in breast cancer patients.

Animal models have demonstrated the critical role of bone marrow-derived VEGFR1(+) hematopoietic progenitor cells (HPCs) and VEGFR2(+) endothelial progenitor cells (EPCs) in metastatic progression. We explored whether these cells could predict relapse and response in breast cancer (BC) patients. One hundred and thirty-two patients with stages 1-4 BC were enrolled on 2 studies.

Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer.

Background: 3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP) is a novel small molecule ribonucleotide reductase (RR) inhibitor which is more potent than hydroxyurea, the prototype of RR inhibitors. 3-AP enhances the cellular uptake and DNA incorporation of gemcitabine in tumor cell lines. We evaluated the combination of 3-AP plus gemcitabine in advanced biliary tract adenocarcinoma.

RD114 envelope proteins provide an effective and versatile approach to pseudotype lentiviral vectors.

Lentiviral vectors derived from the HIV-1 genome offer great promise for gene therapy due to their ability to transduce non-dividing cells and sustain long-term expression of transgenes. The majority of current lentiviral vectors are pseudotyped with the vesicular stomatitis viral envelope (VSV-G). VSV-G equips lentiviral vectors with a broad host cell tropism and increased stability.

Etoposide-initiated MLL rearrangements detected at high frequency in human primitive hematopoietic stem cells with in vitro and in vivo long-term repopulating potential.

Rearrangements initiating within the well-characterized break-point cluster region of the mixed lineage leukemia (MLL) gene on 11q23 are a hallmark of therapy-related leukemias following treatment with topoisomerase II poisons including etoposide. Hematopoietic stem cells (HSC) are believed to be the target cell for leukemia-initiating MLL rearrangement events. Although etoposide treatment is sufficient to induce readily detectable MLL rearrangements in primary human CD34+ cells, the majority of cells that gain translocations do not proliferate in culture possibly due to reduced proliferative capacity of most CD34+ cells during normal differentiation [Blood 2005;105:2124].

Activating Notch1 mutations are an early event in T-cell malignancy of Ikaros point mutant Plastic/+ mice.

Ikaros and Notch1 genes are critical to T-cell differentiation through transcriptional activation of target genes and interaction with chromatin remodeling complexes. An Ikaros (Plastic) point mutation inhibits activity of normal Ikaros and Ikaros family members, and leads to T-cell lymphoma in heterozygotes (Plstc/+). Analysis revealed Notch1 activating mutations in 12 of 17 Plstc/+ lymphomas (70%), analogous to those in human T-ALL.

Ikaros increases normal apoptosis in adult erythroid cells.

Ikaros is a critical transcriptional regulator of hematopoietic cell differentiation. In addition to its effects on the lymphoid system and hematopoietic stem-cell compartment, we have previously shown that Ikaros is also required for normal erythroid development. In this report, we compare Ikaros-dependent gene expression in erythroid cells of mice lacking the Ikaros protein with that of normal mice in purified adult bone-marrow erythroid cells (BMRC).

Role of intergenic human gamma-delta-globin sequences in human hemoglobin switching and reactivation of fetal hemoglobin in adult erythroid cells.

The details of the molecular events regulating normal human hemoglobin switching and reactivation of fetal hemoglobin in adult hematopoietic cells are unclear. The potential role of sequences between the human gamma- and delta-globin genes (intergenic gamma-delta sequences) in this process has been in question until the recent finding that two patients homozygous for the Corfu deletion, involving the loss of 7.2 kb of the intergenic gamma-delta region upstream of the delta gene, have 88% and 90% fetal hemoglobin, only mild anemia, and no transfusion requirements.

A stable murine-based RD114 retroviral packaging line efficiently transduces human hematopoietic cells.

Several barriers exist to high-efficiency transfer of therapeutic genes into human hematopoietic stem cells (HSCs) using complex oncoretroviral vectors. Human clinical trials to date have used Moloney leukemia virus-based amphotropic and gibbon ape leukemia virus-based envelopes in stable retroviral packaging lines. However, retroviruses pseudotyped with these envelopes have low titers due to the inability to concentrate viral supernatants efficiently by centrifugation without damaging the virus and low transduction efficiencies because of low-level expression of viral target receptors on human HSC.

Correction of phenotype in a thalassemia mouse model using a nonmyeloablative marrow transplantation regimen.

Gene therapy, the replacement of normal human beta- or gamma-globin genes into the hematopoietic stem cells of patients with homozygous beta-thalassemia, is a promising therapy for the future. High-level lineage-specific stable globin expression in transduced cells reinfused into patients in an autologous transplantation setting could be curative, if successful. Previous studies have shown high-level donor chimerism in nonmyeloablated non-thalassemic hosts.

Three-year prospective validation of a pre-endoscopic risk stratification in patients with acute upper-gastrointestinal haemorrhage.

Objective: To assess the accuracy of a risk stratification that is used at initial assessment to identify groups with increased risk of mortality and requirement for urgent treatment intervention.

Design: Prospective assessment of risk stratification in consecutive patients with acute upper-gastrointestinal haemorrhage.

Methods: Over a 3-year period, 1349 consecutive patients with acute upper-gastrointestinal haemorrhage presenting to a single teaching hospital were prospectively risk stratified before endoscopy and followed up for outcome.