Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria.

ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder that occurs on a background of bone marrow failure (BMF). In PNH, chronic intravascular hemolysis causes an increase in morbidity and mortality, mainly because of thromboses. Over the last 20 years, treatment of PNH has focused on the complement protein C5 to prevent intravascular hemolysis using the monoclonal antibody eculizumab and more recently ravulizumab. In the United Kingdom, all patients are under review at 1 of 2 reference centers. We report on all 509 UK patients with PNH treated with eculizumab and/or ravulizumab between May 2002 and July 2022. The survival of patients with eculizumab and ravulizumab was significantly lower than that of age- and sex-matched controls (P = .001). Only 4 patients died of thromboses. The survival of patients with PNH (n = 389), when those requiring treatment for BMF (clonal evolution to myelodysplastic syndrome or acute leukemia or had progressive unresponsive aplastic anemia) were excluded, was not significantly different from that of age- and sex-matched controls (P = .12). There were 11 cases of meningococcal sepsis (0.35 events per 100 patient-years). Extravascular hemolysis was evident in patients who received treatment, with 26.7% of patients requiring transfusions in the most recent 12 months on therapy. Eculizumab and ravulizumab are safe and effective therapies that reduce mortality and morbidity in PNH, but further work is needed to reduce mortality in those with concomitant BMF.

Whole-exome sequencing of Indian prostate cancer reveals a novel therapeutic target: POLQ.

PURPOSE: Prostate cancer is the second most common cancer diagnosed worldwide and the third most common cancer among men in India. This study's objective was to characterise the mutational landscape of Indian prostate cancer using whole-exome sequencing to identify population-specific polymorphisms. METHODS: Whole-exome sequencing was performed of 58 treatment-naive primary prostate tumors of Indian origin. Multiple computational and statistical analyses were used to profile the known common mutations, other deleterious mutations, driver genes, prognostic biomarkers, and gene signatures unique to each clinical parameter. Cox analysis was performed to validate survival-associated genes. McNemar test identified genes significant to recurrence and receiver-operating characteristic (ROC) analysis was conducted to determine its accuracy. OncodriveCLUSTL algorithm was used to deduce driver genes. The druggable target identified was modeled with its known inhibitor using Autodock. RESULTS: TP53 was the most commonly mutated gene in our cohort. Three novel deleterious variants unique to the Indian prostate cancer subtype were identified: POLQ, FTHL17, and OR8G1. COX regression analysis identified ACSM5, a mitochondrial gene responsible for survival. CYLC1 gene, which encodes for sperm head cytoskeletal protein, was identified as an unfavorable prognostic biomarker indicative of recurrence. The novel POLQ mutant, also identified as a driver gene, was evaluated as the druggable target in this study. POLQ, a DNA repair enzyme implicated in various cancer types, is overexpressed and is associated with a poor prognosis. The mutant POLQ was subjected to structural analysis and modeled with its known inhibitor novobiocin resulting in decreased binding efficiency necessitating the development of a better drug. CONCLUSION: In this pilot study, the molecular profiling using multiple computational and statistical analyses revealed distinct polymorphisms in the Indian prostate cancer cohort. The mutational signatures identified provide a valuable resource for prognostic stratification and targeted treatment strategies for Indian prostate cancer patients. The DNA repair enzyme, POLQ, was identified as the druggable target in this study.

A Rare Case of Severe Hemolytic Anemia and Pulmonary Embolism Secondary to Mycoplasma pneumoniae Infection.

A 27-year-old woman was admitted with a history of dry cough, breathlessness, fever, lethargy, and nausea and vomiting. On examination, she was febrile, jaundiced, and hypoxic. Blood tests revealed severe leucocytosis and severe hemolytic anemia. The chest imaging demonstrated coexisting pneumonia and pulmonary embolism. An initial blood transfusion worsened the hemolytic anemia to the point that critical care review was required. Subsequent blood tests revealed cold agglutinin hemolytic anemia due to Mycoplasma pneumoniae infection. The patient's condition improved after receiving a warm-blood transfusion, antibiotics, and steroid therapy. The patient also received anticoagulant therapy for 6 months. Our case is unique in that the patient had very severe anemia and very severe leucocytosis, making us suspect a hematologic malignancy at initial presentation. This case emphasizes the importance of prompt evaluation of hemolytic anemia and the use of warm blood transfusion for cold agglutinin disease.

Environmental sustainability assessment of tropical dairy buffalo farming vis-a-vis sustainable feed replacement strategy.

Feeding management in dairy animals is crucial for ensuring optimal production apart from making the farming as a whole, a more sustainable activity. In our study we evaluated the production and environmental effects of two different feeding regimens i.e., one dominated by traditional cottonseed meal (CSM) and other with coated urea (slow release urea - SRU) as a replacement for CSM on dairy buffalo production. The SRU at 2% level was evaluated by conducting two different trials using twelve lactating Murrah buffaloes and four adult Murrah buffalo bulls. Neither diet nor dry period management showed any substantial effect on milk components, intakes, nutrients' digestibility coefficients, and nutritive values. The SRU diet revealed increased (P < 0.01) rumen pH, ammonia nitrogen, volatile fatty acids, and microbial nitrogen yield, which were interacted with time of post-prandial sampling. The dynamics of nitrogen metabolism revealed unaltered N-based parameters, except for degradable-N intake and serum urea-N at 3 hr post-feeding. The CSM replacements did not influence (P > 0.05) the residual feed intake, but led to an enhanced milk retention efficiency of nitrogen, calcium, and phosphorus contents, thus reducing their impact on soil pollution and eutrophication of water bodies. Despite an unaltered (P > 0.05) enteric methane emission, SRU diets achieved in decreasing manure methane and nitrous oxide emission. Furthermore, the virtual water flow and lifecycle assessment revealed a water sparing effect and low carbon foot print per unit milk production. In summary, the CSM replacements with SRU could achieve an economical and eco-friendly production system from animal nutrition perspective.

Assessment of eco-sustainability vis-à-vis zoo-technical attributes of soybean meal (SBM) replacement with varying levels of coated urea in Nellore sheep (Ovis aries).

The contemporary environmental-stewardship programmes primarily aimed at curbing the global warming potential by adopting a multidisciplinary approach. Manipulating the feeding strategies has great potential in reducing the environmental footprints of livestock production. This study intends to assess the effect of soybean meal (SBM) replacement with varying levels of coated urea (SRU) on both zoo-technical (nutrient digestibility, heat increment, and physio-biochemical parameters) and environmental attributes. The coated urea was used to replace the SBM at 0, 25, 50, and 75 percent levels. Eight adult rams (43.02 ± 0.76) maintained in a conventional shed were used in a replicated 4 x 4 Latin square design. Not all the physiological parameters viz. rectal temperature, pulse rate, and respiratory rate were affected (P>0.05)f by varying levels of SRU incorporation. The SRU fed animals had higher (P<0.05) crude protein digestibility compared to SBM fed animals; however, the replacements did not affect the nutrient digestibility coefficients of DM, OM, NFC, NDFap, ADF, and hemicellulose components. The SRU did not affect various biochemical parameters such as serum glucose, total protein, albumin, globulin, urea, creatinine, ALT, AST, Ca, P and T3, and T4 levels; however, post-prandial serum urea N (SUN) values showed a diurnal quadratic pattern (P<0.05) with a dose-dependent relationship. Further, the SBM replacements had no effect on the calcium excretion, while the SRU incorporation decreased the faecal phosphorous content, thereby abating the eutrophication phenomenon. Although the SBM replacements did not affect in vivo water variables and faecal solid fractions, they managed to decrease the land and virtual water requirement along with global warming potential (GWP) of the entire trial. The GWP-perceptual map unveils the fact that replacement of conventional feed ingredients with NPN compounds aids in eco-friendly livestock production. Further, the conjectural analysis of the carbon footprint methodology revealed that agricultural by-products consideration could cause a huge increase in the GWP share of feed consumed, thus compelling the importance of research pertaining to feed production perspective as equal as ruminal methane amelioration.

Thyroid dysfunction in preterm neonates exposed to iodine.

BACKGROUND: Infants <32 weeks' gestation should not be exposed to topical iodine and its avoidance is recommended during pregnancy and breast feeding. Exposure to contrast media and topical iodine is frequently used in many preterm neonates. AIM: To determine whether thyrotropin levels in preterm infants are affected by exposure to intrapartum/neonatal topical iodine and/or the use of iodinated contrast media. DESIGN: Infants <32 weeks' gestation were recruited. Maternal and neonatal exposures to iodinated contrast media and topical iodine were recorded; levels of thyrotropin and thyroxine were measured from blood-spot cards on postnatal days 7, 14, 28 and the equivalent of 36 weeks' gestation. RESULTS: One hundred and twenty-five infants were exposed to topical iodine/contrast media and 48 infants were unexposed. No infants were treated for hypothyroidism; three infants (exposed group) had transient hyperthyrotropinaemia. Mean thyrotropin levels were significantly higher on postnatal days 7, 14 and 28 in infants exposed to topical iodine prior to caesarean section compared to unexposed infants, a relationship which persisted after adjustment. CONCLUSIONS: In the context of this study, neonatal thyroid dysfunction was seen following exposure to iodine via caesarean section but not via exposure to contrast media.

MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer.

Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3ε to prostate cancer cells expressing PSMA (prostate-specific membrane antigen). In vitro cross-linking of T cells with PSMA-expressing tumor cells by MOR209/ES414 triggered potent target-dependent tumor lysis and induction of target-dependent T-cell activation and proliferation. This activity occurred at low picomolar concentrations of MOR209/ES414 and was effective at low T-effector to tumor target cell ratios. In addition, cytotoxic activity was equivalent over a wide range of PSMA expression on target cells, suggesting that as few as 3,700 PSMA receptors per cell are sufficient for tumor lysis. In addition to high sensitivity and in vitro activity, MOR209/ES414 induced limited production of cytokines compared with other bispecific antibody formats. Pharmacokinetic analysis of MOR209/ES414 demonstrated a serum elimination half-life in NOD/SCID γ (NSG) mice of 4 days. Administration of MOR209/ES414 in murine xenograft models of human prostate cancer significantly inhibited tumor growth, prolonged survival, and decreased serum prostate-specific antigen levels only in the presence of adoptively transferred human T cells. On the basis of these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC. Mol Cancer Ther; 15(9); 2155-65. ©2016 AACR.

Intracranial metastasis from primary spinal primitive neuroectodermal tumor.

Primary spinal primitive neuroectodermal tumors (PNET) are rare tumors, with only 94 cases reported till date. Metastasis to brain from a spinal PNET is even rarer. In the present report, we evaluate the pathology and treatment of solitary intracranial metastasis from spinal PNET in a 22-year-old female who presented with headache and left hemiparesis and was diagnosed to have right parietal parasagittal tumor. She has been previously diagnosed to have cervicothoracic primary spinal PNET, and was treated by surgery, radiotherapy, and chemotherapy seven years back. The intracranial tumor has been removed and pathological examination confirmed as PNET. She received radiotherapy and chemotherapy with ifosfamide and etoposide, following surgery for the right parietal PNET. At 20 months follow-up, patient is stable and has no recurrence of the disease. Critical review of reported cases of primary spinal PNET metastsising to brain was done.

Colonic squamous cell carcinoma in ulcerative colitis: Report of a case and review of the literature.

Squamous cell carcinoma (SCC) is a rare neoplasm in the colorectum. A case of SCC rising from an area of squamous metaplasia in the rectum is presented in a patient with long-standing ulcerative colitis and perianal warts. This is the first report in the literature describing the evolution of squamous metaplasia in the colonic mucosa into invasive carcinoma over time. Related literature on colorectal SCC and squamous metaplasia, and their relationships with inflammatory bowel disease and human papilloma virus, is reviewed.

Is there a role for chemoradiation in the management of cystadenocarcinoma of the pancreas?

Despite a paucity of data, cystadenocarcinoma of the pancreas has been considered to be resistant to chemoradiation, with a limited effect similar to that of the more common pancreatic adenocarcinoma. We describe a case of a partially excised cystadenocarcinoma with a positive surgical margin that was treated by neoadjuvant chemoradiation. No epithelial elements were found on histologic examination after reresection. Three previous cases of dramatic response of pancreatic cystadenocarcinoma to chemoradiation have been described in the literature. The current dogma alleging poor response of pancreatic cystadenocarcinoma to chemoradiation may be in error.

Fixed dose combinations for tuberculosis: Lessons learned from clinical, formulation and regulatory perspective.

Worldwide, tuberculosis (TB) remains one of the most important communicable diseases in terms of morbidity and mortality. Its control requires multi-drug therapy for at least six months, which could lead to patient non-compliance, failure of therapy and ultimately resulting in the emergence of drug resistance. Fixed dose combinations (FDCs) in TB therapy reduce the number of tablets to be consumed and thereby increase patient compliance with recommended treatment regimens. Thus, FDCs play a significant role in preventing the emergence of drug resistance and successful treatment. However, the quality of FDCs with respect to variable bioavailability and their registration requirements are major hurdles to their implementation in national TB control programs. It is anticipated that a large global market for FDCs will encourage large-scale production and increased competition, which in turn will result in FDCs at affordable prices. The Global Drug Facility (GDF), established by the World Health Organization (WHO), aims to ensure universal uninterrupted access to quality TB drugs for implementation of directly observed treatment short-course (DOTS) in resource-poor countries. In this program, four FDCs were accepted as the drugs of first choice because of their obvious advantages in controlling TB. This demands the necessity of addressing quality and registration requirements of FDCs systematically. In light of this current knowledge on anti-TB FDCs, their dosage, combinations, available clinical studies and the experiences with TB therapy has been discussed in this article, which should serve as lessons for selection of appropriate FDCs for other diseases such as malaria and AIDS.