Targeting the ataxia telangiectasia and Rad3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects and replication stress, including inactivation of ataxia telangiectasia mutated (ATM) signaling. We report the dose-escalation portion of the phase I first-inhuman trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5-80 mg twice daily (BID) in 21 patients with advanced solid tumors. The maximum tolerated dose was 40 mg BID 3 days on/4 days off. Commonest adverse events were manageable and reversible hematological toxicities. Partial responses were achieved in 4 patients and stable disease in 8 patients. Median duration of response was 315.5 days. Responders had ATM protein loss and/or deleterious ATM mutations and received doses 40 mg BID. Overall, BAY 1895344 is well tolerated with antitumor activity against cancers with certain DDR defects, including ATM loss. An expansion phase continues in patients with DDR deficiency. SIGNIFICANCE Oral BAY 1895344 was tolerable with antitumor activity in heavily pre-treated patients with various advanced solid tumors, particularly those with ATM deleterious mutations and/or loss of ATM protein; pharmacodynamic results supported a mechanism of action of increased DNA damage. Further study is warranted in this patient population.

Poultry is an imperative domesticated livestock species that provides high quality protein and micronutrients as meat and eggs. In poultry production, feed is the single major input constituting 70–75% of total production cost. Feed mainly consists of cereal grains, those provide energy to the birds. However, these grains contain different levels of anti-nutritional factors such as non-starch polysaccharides (NSP). These NSP are indigestible by poultry birds due to the lack of vital endogenous enzymes (carbohydrases) thus increase intestinal viscosity which slower the migration and absorption of nutrients. Consequently, these NSP may also increase the chances for infection by inducing competition within gut microbiota for digestible nutrients. This affects bird's health and increases the production cost. Therefore, there is a need to find efficient and effective solutions for these problems. Carbohydrases supplementation have an important role in poultry diets with high NSP contents. Feed enzymes are being used from years to enhance growth performance and digestibility but have limited activity for selective ingredients. New generation carbohydrases with a board range of activity and stability help to degrade the complex substrates and improve growth performance of poultry. Present review summarizes the updated literature on the use of carbohydrases to improve bird's performance and intestinal health.

BackgroundUropathogenic E.coli (UPEC) are among major pathogens causing urinary tract infections. Virulence factors are mainly responsible for the severity of these emerging infections. This study was planned to investigate the distribution of virulence genes and cytotoxic effects of UPEC isolates with reference to phylogenetic groups (B2, B1, D and A) to understand the presence and impact of virulence factors in the severity of infection in Faisalabad region of Pakistan.MethodsIn this study phylogenetic analysis, virulence gene identification and cytotoxicity of 59 uropathogenic E.coli isolates obtained from non-hospitalized patients was studied.ResultsAmong 59 isolates, phylogenetic group B2 (50%) was most dominant followed by groups A, B1 (19% each) and D (12%). Isolates present in group D showed highest presence of virulence genes. The prevalence hlyA (37%) was highest followed by sfaDE (27%), papC (24%), cnf1 (20%), eaeA (19%) and afaBC3 (14%). Highly hemolytic and highly verotoxic isolates mainly belonged to group D and B2. We also found two isolates with simultaneous presence of three fimbrial adhesin genes present on pap, afa, and sfa operons. This has not been reported before and underlines the dynamic nature of these UPEC isolates.ConclusionsIt was concluded that in local UPEC isolates from non-hospitalized patients, group B2 was more prevalent. However, group D isolates were most versatile as all were equipped with virulence genes and showed highest level of cytotoxicity.

BackgroundDengue epidemic in Lahore (2011) resulted in hundreds of deaths and affected thousands. As most of the studies were focused on its diagnosis and treatment, scanty data is available on associated diseases/co-morbidities in these patients that could have contributed to a higher mortality. There were no local guidelines available on recording, reporting and management of these co-morbidities. The objective of this study was to analyze the initial presentations of dengue cases and to estimate the frequency of co-morbidities in dengue patients.MethodsData of 556 dengue cases was retrieved from 2 major public sector tertiary-care hospitals for patients who were admitted during 2011 epidemic and a case record analysis was done. Data was retrieved from patient’s information reports which included demography, signs and symptoms and the laboratory investigations. In addition verbal autopsy of deceased cases was also done from their relatives using standardized WHO verbal autopsy form after making modifications as per needed.ResultsOf 556 cases studied, 390 (70%) were males. The mean age was 36 years and 30% of the cases were between 20-29 years. Average duration of the hospital stay was 6 days. Out of the total, 435 (78%) were dengue fever (DF) cases followed by dengue hemorrhagic fever (DHF) in 95 (17%) and dengue shock syndrome (DSS) in 26 (4%) cases. A total of 40 cases died and among them 17 were diagnosed with DSS, 13 DF and 10 DHF. Further the verbal autopsy from relatives of deceased cases showed 29 (60%) deceased had co-morbid diseases which included hypertension, diabetes etc. DSS was common in patients who had hypertension (27) either alone or associated with other illnesses.ConclusionsCo-morbidities with dengue infection were seen in 60% deceased cases indicating the reasons for high dengue related complications and death.