Descriptive analysis and prognostic factors in cats with myeloma-related disorders: A multicenter retrospective study of 50 cases.

BACKGROUND: Myeloma-related disorders (MRDs) are rare and poorly documented neoplasms of cats. HYPOTHESIS/OBJECTIVES: To describe clinical, clinicopathologic, and imaging findings, response to treatment, and survival time and to identify factors associated with shorter outcomes in cats with MRD. ANIMALS: Fifty cats with a diagnosis of MRD. METHODS: Cats with paraproteinemia confirmed by serum protein electrophoresis (SPE) and either intramedullary plasmacytosis >10%, marked cytonuclear atypia with intramedullary plasmacytosis that ranged between 5% and 10%, or cytologically or histologically confirmed visceral infiltration were retrospectively included from several veterinary referral centers. RESULTS: Bone marrow plasmacytosis and splenic or hepatic involvement were present in 17/27 cats (63%), 36/42 cats (86%), and 27/38 cats (71%), respectively. Anemia was reported in 33/49 cats (67%) and thrombocytopenia in 16/47 cats (34%). Some of the treatments that the cats received included melphalan and prednisolone (n = 19), cyclophosphamide and prednisolone (n = 10), chlorambucil and prednisolone (n = 4), prednisolone (n = 4), or other (n = 4). The overall response rates to melphalan, cyclophosphamide, and chlorambucil in combination with prednisolone were 87%, 90%, and 100%, respectively. Adverse events to melphalan or cyclophosphamide occurred in 65% and 23% of cats, respectively. Median survival time was 122 days (range, 0-1403) and was not significantly associated with chemotherapy protocol. Anemia (hazard ratio [HR], 3.1; 95% confidence interval [CI], 1.0-9.8) and thrombocytopenia (HR, 2.7; 95% CI, 1.2-6.0) were risk factors for shorter survival. CONCLUSIONS AND CLINICAL IMPORTANCE: Our study confirmed the guarded prognosis of MRD in cats and identified risk factors for shorter survival times.

CRISPR screening identifies BET and mTOR inhibitor synergy in cholangiocarcinoma through serine glycine one carbon.

Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anticancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the 2 inhibitor classes converged on H3K27ac-marked epigenetic suppression of the serine glycine one carbon (SGOC) metabolism pathway, including the key enzymes PHGDH and PSAT1. Knockdown of PSAT1 was sufficient to replicate synergy with single-agent inhibition of either BET or mTOR. Our results tie together epigenetic regulation, metabolism, and apoptosis induction as key therapeutic targets for further exploration in this underserved disease.

Effect of Salt Concentration on Oil Recovery during Polymer Flooding: Simulation Studies on Xanthan Gum and Gum Arabic.

Oil recoveries from medium and heavy oil reservoirs under natural recovery production are small because of the high viscosity of the oil. Normal water flooding procedures are usually ineffective, as the injected water bypasses much of the oil because of its high mobility. Thermal flooding processes are desirable but have many disadvantages from costs, effects on the environment, and loss of lighter hydrocarbons. Chemical flooding options, such as bio-polymer flooding options, are attractive, as they are environmentally friendly and relatively cheap to deploy and help to increase the viscosity of the injecting fluid, thereby reducing its mobility and increasing its oil recovery. The downside to polymer flooding includes reservoir temperature, salinity, molecular weight, and composition. Six weight percentages of two polymers (xanthan gum, XG, and gum arabic, GA) are dissolved in water, and their viscosity is measured in the laboratory. These viscosities are incorporated with correlations in the Eclipse software to create models with different polymer concentrations of (0.1% wt., 0.2% wt., 0.3% wt., 0.4% wt., 0.5% wt., and 1% wt.). A base case of natural recovery and water injection was simulated to produce an oil recovery of 5.9% and 30.8%, respectively, while at 0.1% wt. and 1% wt., respectively, oil recoveries of 38.8% and 45.7% (for GA) and 48.1% and 49.8% (for XG) are estimated. At 5% and 10% saline conditions, a drop in oil recovery of (4.6% and 5.3%) is estimated during GA flooding and (1.2% and 1.7%) for XG flooding at 1% wt., respectively. XG exhibits higher oil recoveries compared to GA at the same % wt., while oil recoveries during GA floodings are more negatively affected by higher saline concentrations.

Calculation of dose intensity and comparison of published methods using a cohort of canine T-cell lymphoma patients undergoing CHOP-based chemotherapy.

Methods of calculating and reporting dose intensity (DI) of CHOP-based protocols in the veterinary literature vary. The goal of this retrospective study is to examine the prognostic significance of the average percentage of planned DI received in a cohort of canine T-cell lymphoma patients treated with a modified CHOP protocol with corresponding toxicity and efficacy data. Our data set of 40 dogs was analysed using various previously published methods for calculating DI. Median progression-free survival and overall survival were 91 and 196 days, respectively. Receiving a higher percentage of planned DI was not found to be associated with patient outcome. Outcomes remain poor for dogs with T-cell lymphoma treated with CHOP-based chemotherapy irrespective of received DI. Standard methods of DI calculation and reporting should be adopted in veterinary oncology to enable repeatable and rigorous comparisons of published chemotherapy protocols and to ascertain the potential prognostic relevance of DI in canine lymphoma patients.

Macrophage mediated recognition and clearance of Borrelia burgdorferi elicits MyD88-dependent and -independent phagosomal signals that contribute to phagocytosis and inflammation.

BACKGROUND: Macrophages play prominent roles in bacteria recognition and clearance, including Borrelia burgdorferi (Bb), the Lyme disease spirochete. To elucidate mechanisms by which MyD88/TLR signaling enhances clearance of Bb by macrophages, we studied wildtype (WT) and MyD88-/- Bb-stimulated bone marrow-derived macrophages (BMDMs). RESULTS: MyD88-/- BMDMs exhibit impaired uptake of spirochetes but comparable maturation of phagosomes following internalization of spirochetes. RNA-sequencing of infected WT and MyD88-/- BMDMs identified a large cohort of differentially expressed MyD88-dependent genes associated with re-organization of actin and cytoskeleton during phagocytosis along with several MyD88-independent chemokines involved in inflammatory cell recruitment. We computationally generated networks which identified several MyD88-dependent intermediate proteins (Rhoq and Cyfip1) that are known to mediate inflammation and phagocytosis respectively. CONCLUSION: Our findings show that MyD88 signaling enhances, but is not required, for bacterial uptake or phagosomal maturation and provide mechanistic insights into how MyD88-mediated phagosomal signaling enhances Bb uptake and clearance.

Response-based modification of CHOP chemotherapy for canine B-cell lymphoma.

Despite high initial response rates, a subset of dogs with B-cell lymphoma responds less robustly to CHOP-based chemotherapy and experiences shorter survival. One hundred and four dogs with nodal B-cell lymphoma were treated with a response-based CHOP (RBCHOP) protocol modified based on response to individual drugs during the first chemotherapy cycle. Dogs achieving complete (CR) or partial response (PR) at week 3, following treatment with vincristine and cyclophosphamide, received RBCHOP 1 (n = 72), a protocol sequentially rotating vincristine, cyclophosphamide, and doxorubicin. Dogs without a detectable response at week 3 that subsequently achieved CR or PR following treatment with doxorubicin received RBCHOP 2 (n = 14), in which four doses of doxorubicin were given consecutively followed by vincristine and cyclophosphamide. Dogs that failed to respond at week 3 and then to doxorubicin at week 5 assessment were offered rescue chemotherapy (RBCHOP 3, n = 18). Median progression free survival (PFS) and overall survival time (OST) were similar between RBCHOP 1 (PFS 210 days, OST 354 days) and RBCHOP 2 (PFS 220 days, OST 456 days), but significantly shorter for RBCHOP 3 (PFS 34 days, OST 80.5 days, P < 0.001). No presenting signalment nor hematologic variable differentiated patient cohort, however, dogs in RBCHOP 2 and RBCHOP 3 were more likely to have a lymphocytosis at diagnosis (P = 0.02 and 0.04, respectively). Protocol modification based on response during the first cycle resulted in similar toxicity profiles and outcomes to previously published variants of CHOP, and prognosis remained poor for dogs failing to respond during the first treatment cycle.

Retrospective evaluation of risk factors and treatment outcome predictors in cats presenting to the emergency room for constipation.

OBJECTIVES: Constipation is a common complaint in cats presenting to the emergency room and can become a frustrating recurrent condition. Despite widespread anecdotal reports of risk factors for constipation, at the time of writing there have been no studies supporting these associations or assessing treatment outcomes. The aim of this study was to identify risk factors in the signalment, history, physical examination and clinicopathologic findings of cats presenting to the emergency room for constipation. In addition, we aimed to assess factors contributing to the success or failure of enemas administered to these cats. METHODS: A medical record search identified 189 cats with a diagnosis of constipation/obstipation that were treated and discharged by the emergency service at an academic veterinary hospital. Data regarding signalment, medical history, physical examination and clinicopathologic findings, as well as treatments performed, were recorded. Ninety-nine cats presenting to the emergency room for other reasons were identified as controls. Statistical analysis was performed to assess risk factors for constipation, as well as success/failure of enema treatments. RESULTS: Older, overweight cats and cats with chronic kidney disease or previous episodes of constipation were found to be at increased risk of constipation (P <0.0001, P = 0.0004, P = 0.0046 and P <0.0001, respectively). Ionized calcium levels were significantly higher in constipated cats, though varied significantly within the cohort (P = 0.0133). Cats noted to be painful on abdominal palpation were less likely to defecate following an enema. Adjunctive treatments (fluids, laxatives) increased the likelihood of a successful enema but were not statistically significant. CONCLUSIONS AND RELEVANCE: Older, overweight cats with a history of constipation or chronic kidney disease are more likely to present for constipation. Further studies are needed to determine the most appropriate treatment protocol in an urgent care setting.

IFNγ Enhances CD64-Potentiated Phagocytosis of Treponema pallidum Opsonized with Human Syphilitic Serum by Human Macrophages.

Syphilis is a multi-stage, sexually transmitted disease caused by the spirochete Treponema pallidum (Tp). Considered broadly, syphilis can be conceptualized as a dualistic process in which spirochete-driven inflammation, the cause of clinical manifestations, coexists to varying extents with bacterial persistence. Inflammation is elicited in the tissues, along with the persistence of spirochetes to keep driving a robust immune response while evading host defenses; this duality is best exemplified during the florid, disseminated stage called secondary syphilis (SS). SS lesions typically contain copious amounts of spirochetes along with a mixed cellular infiltrate consisting of CD4+ T cells, CD8+ T cells, NK cells, plasma cells, and macrophages. In the rabbit model, Tp are cleared by macrophages via antibody-mediated opsonophagocytosis. Previously, we demonstrated that human syphilitic serum (HSS) promotes efficient uptake of Tp by human monocytes and that opsonophagocytosis of Tp markedly enhances cytokine production. Herein, we used monocyte-derived macrophages to study Tp-macrophage interactions ex vivo. In the absence of HSS, monocyte-derived macrophages internalized low numbers of Tp and secreted little cytokine (e.g., TNF). By contrast, these same macrophages internalized large numbers of unopsonized Borrelia burgdorferi and secreted robust levels of cytokines. Maturation of macrophages with M-CSF and IFNγ resulted in a macrophage phenotype with increased expression of HLA-DR, CD14, inducible nitric oxide synthase, TLR2, TLR8, and the Fcγ receptors (FcγR) CD64 and CD16, even in the absence of LPS. Importantly, IFNγ-polarized macrophages resulted in a statistically significant increase in opsonophagocytosis of Tp accompanied by enhanced production of cytokines, macrophage activation markers (CD40, CD80), TLRs (TLR2, TLR7, TLR8), chemokines (CCL19, CXCL10, CXCL11), and TH1-promoting cytokines (IL-12, IL-15). Finally, the blockade of FcγRs, primarily CD64, significantly diminished spirochetal uptake and proinflammatory cytokine secretion by IFNγ-stimulated macrophages. Our ex vivo studies demonstrate the importance of CD64-potentiated uptake of opsonized Tp and suggest that IFNγ-activated macrophages have an important role in the context of early syphilis. Our study results also provide an ex vivo surrogate system for use in future syphilis vaccine studies.

Devising a Method to Study if Wernicke's Aphasia Patients are Aware That They Do Not Comprehend Language or Speak It Understandably.

Wernicke's Aphasia (WA) is characterized by an individual speaking fluent gibberish without the ability to understand anything that is said to them or anything they attempt to read. It is caused by damage to the left posterior temporoparietal cortex, also known as Wernicke's area. An additional intriguing symptom of WA patients is their apparent obliviousness to their own lack of understanding despite their intact reasoning or other cognitive abilities. Their only deficit seems to be in the basic rules of language that define word meaning, also known as phonology. Growing out of a project in an undergraduate class, we devised a phonology-free approach to communicating with WA patients that attempts to answer the questions of whether WA patients know that they do not understand what is said to them, that others do not understand what they have said, and if these patients are distressed by this lack of communication. We here describe the process and the resulting method.

Stroke in a young patient with neurosyphilis and HIV.

Syphilis has long been known as the great imitator. Its heterogeneity can manifest in the form of meningitis, space occupying gummas, vasculitis, strokes, cranial neuropathies, myelopathy, dementia, and seizures. The incidence has been rising with each year, mainly in men who have sex with men accounting for 83% of cases. With the coexistence of immunocompromised states, especially HIV (human immunodeficiency virus), the usually chronic and insidious course of tertiary neurosyphilis can be accelerated. Stroke can occur as a result of neurosyphilis in its meningovascular form, and the likelihood of this increases with HIV co-infection, especially in high-risk groups such as intravenous drug users and men who have sex with men. Here, we discuss a case of a young man who presented with an ischemic stroke found to have neurosyphilis and HIV and consider the management of these co-morbid conditions.

Isolated, relative aproverbia without focal lesion.

We have seen a patient with a profound, isolated, and quite selective deficit in proverb interpretation-aproverbia. The patient presented to us after an anoxic brain injury with aproverbia. Interestingly, the aproverbia appeared to be premorbid to the presenting event. Furthermore, the patient had no brain lesion that has been associated or even proposed as a cause of deficit in proverb or metaphor interpretation. The patient did have acute bilateral hippocampi lesions and associated severe anterograde amnesia, but he retained good retrograde memory with which he is able to give good, logical but concrete explanations for proverbs. This case highlights the need, importance, and interest in further neuropsychologic, imaging and functional studies of proverb and interpretation in patients and normal subjects populations.

Phagosomal TLR signaling upon Borrelia burgdorferi infection.

Internalization and degradation of live Bb within phagosomal compartments of monocytes, macrophages and dendritic cells (DCs), allows for the release of lipoproteins, nucleic acids and other microbial products, triggering a broad and robust inflammatory response. Toll-like receptors (TLRs) are key players in the recognition of spirochetal ligands from whole viable organisms (i.e., vita-PAMPs). Herein we will review the role of endosomal TLRs in the response to the Lyme disease spirochete.

A role for the copper transporter Ctr1 in the synergistic interaction between hyperthermia and cisplatin treatment.

PURPOSE: Hyperthermia enhances cytotoxic effects of chemotherapeutic agents such as cisplatin. However, the underlying molecular mechanisms remain unclear. We hypothesised that hyperthermia increases cisplatin accumulation and efficacy by modulating function of copper transport protein 1 (Ctr1), a major regulator of cellular cisplatin uptake. We examined the significance of Ctr1 in the synergistic interaction between hyperthermia and cisplatin. We assessed the importance of cisplatin- and hyperthermia-induced Ctr1 multimerisation in sensitising cells to cisplatin cytotoxicity. MATERIALS AND METHODS: Ctr1 protein levels and cisplatin sensitivities were assessed in bladder cancer cell lines with immunoblotting and clonogenic survival assays. Using Myc-tagged-Ctr1 HEK293 cells, we assessed the effect of hyperthermia on Ctr1 multimerisation with immunoblotting. The effect of hyperthermia on cisplatin sensitivity and accumulation was assessed in wild-type (WT) and Ctr1 knockout (Ctr1-/-) mouse embryonic fibroblasts (MEFs) with clonogenic assays and inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: Increased Ctr1 protein expression was observed for the most cisplatin-sensitive bladder cancer cell lines and MEFs. Heat-induced increase in Ctr1 multimerisation with cisplatin was observed in Myc-tagged Ctr1 cells. Hyperthermia enhanced cisplatin-mediated cytotoxicity in WT more than Ctr1-/- cells (dose modifying factors 1.75 versus 1.4, respectively). WT cells accumulated more platinum versus Ctr1-/- cells; this was further increased by hyperthermia in WT cells. CONCLUSIONS: Hyperthermia enhanced cisplatin uptake and cytotoxicity in WT cells. Heat increased Ctr1 activity by increasing multimerisation, enhancing drug cytotoxicity. Furthermore, Ctr1 protein profiles of bladder tumours, as well as other tumour types, may predict their response to cisplatin and overall efficacy of treatment.