The global landscape of availability, accessibility and affordability of essential diagnostics and therapeutics for the management of HER2-positive breast cancer: The ONCOLLEGE-001 survey.

AIM OF THE STUDY: Barriers in access to essential care are key determinants of disparities in cancer survival. Breast cancer (BC) is the most common cancer and lead cause of mortality among women, 60 % occurring in low- and middle-income countries (LMs). A quarter of BC are characterized by an over-expression of the epidermal growth factor receptor 2 (HER2). Valuable strategies to diagnose and manage patients with HER2-positive BC have been determined and some considered essential health interventions. ONCOLLEGE-001 is a global survey of availability, accessibility, and affordability of essential HER2 diagnostics and therapeutics. METHOD: A self-administered questionnaire was shared electronically to oncologists, identified from oncology networks. Data were analyzed using descriptive statistics, per income areas and geographic regions. RESULTS: We received 191 responses (84 % response rate). The majority of the responders were from LMs (n = 153) and were physician providers. Immunohistochemistry was the most common HER2 diagnostics available (n = 185). A third of the responders from low/lower-middle and a half of upper-middle income countries had HER2 testing only in the private sector. Trastuzumab was not available for 8 %: when available, 15%-21% reported accessibility only as out-of-pocket expenditure; when not reimbursed, only 10 % of the providers could significantly offer this intervention. Availability of trastuzumab biosimilars was reported in more than a half of the responders (n = 107). CONCLUSION: Stark disparities are reported, with high out-of-pocket expenses for HER2 testing and significant financial barriers to access trastuzumab treatments. Policy solutions are urgently warranted for the selection, prioritization, and reimbursement of essential health interventions, to result in improved population health. POLICY SUMMARY STATEMENT: the inclusion of essential services for cancer management should be assured and financed in the benefit packages of healthcare to all. Prioritizing high-value health interventions, including medicines and medical devices, is critical to deliver impactful programs on population health.

Effect of selenium foliar spray on physiological and biochemical processes and chemical constituents of wheat under drought stress.

Selenium (Se) is considered an essential micronutrient for humans, animals and plants due to its physiological and antioxidative properties. The positive role of Se in attenuation of drastic effects of various environmental stresses in plants is, however, still unclear and need to be explored. The present study aimed at investigating the physiological and biochemical changes induced by Se foliar spray to improve the drought tolerance potential of wheat. Additionally, we also examined the effect of supplemental Se on uptake of nutrients using detection by ICP-OES. Foliar Se application significantly lowered osmotic potential (13%) that markedly improved turgor by 63%, enhanced transpiration rate (60%), improved accumulation of total soluble sugars (33%) and free amino acids (118%) and activity of antioxidant system which ultimately increased the grain yield by 24%. Supplemental Se also significantly increased Se contents (5.77µgg(-1)DW) and improved Fe (91%) and Na (16%) uptake, whereas it reduced Zn accumulation by 54% and did not affect Ca contents. The results supported our hypothesis that supplemental Se influences nutrients uptake and wheat yield through maintenance of turgor and gas exchange characteristics and enhancement in antioxidant system activity.

Effect of therapeutic ultrasound on calcific supraspinatus tendinitis.

Calcific tendinitis is an important cause of shoulder pain. There are various modalities used to treat calcific tendinitis. Ultra-Sound therapy (UST) is a non-invasive modality of treatment. It is not costly. The aims of the present study were to see the efficacy of UST on calcific tendonitis. This was a prospective study done at BSMMU, BIRDEM and Rangpur Medical College Hospital. All the cases with duration of illness more than three months, and diameter of stones more than 5mm were included in this study. Out of 26 cases 10(38%) were male, 14(54%) were housewife, 8(31%) were businessmen. UST were given to all cases for 10 minute with 1 to 1.5 W/sq cm for 12 doses. After 12 doses of UST all the patients became free from pain and restriction of movements. Radiographs of 24(92%) cases showed no calculi. Only two patients showed clinical improvement only but radiographs showed no change in caiculi and symptoms returned after one and two months respectively.

Inhibition of the SERCA Ca2+ pumps by curcumin. Curcumin putatively stabilizes the interaction between the nucleotide-binding and phosphorylation domains in the absence of ATP.

Curcumin is a compound derived from the spice, tumeric. It is a potent inhibitor of the SERCA Ca2+ pumps (all isoforms), inhibiting Ca2+-dependent ATPase activity with IC50 values of between 7 and 15 microm. It also inhibits ATP-dependent Ca2+-uptake in a variety of microsomal membranes, although for cerebellar and platelet microsomes, a stimulation in Ca2+ uptake is observed at low curcumin concentrations (<10 microm). For the skeletal muscle isoform of the Ca2+ pump (SERCA1), the inhibition of curcumin is noncompetitive with respect to Ca2+, and competitive with respect to ATP at high curcumin concentrations ( approximately 10-25 microm). This was confirmed by ATP binding studies that showed inhibition in the presence of curcumin: ATP-dependent phosphorylation was also reduced. Experiments with fluorescein 5'-isothiocyanate (FITC)-labelled ATPase also suggest that curcumin stabilizes the E1 conformational state. The fact that FITC labels the nucleotide binding site of the ATPase (precluding ATP from binding), and the fact that curcumin affects FITC fluorescence indicate that curcumin must be binding to another site within the ATPase that induces a conformational change to prevent ATP from binding. This observation is interpreted, with the aid of recent structural information, as curcumin stabilizing the interaction between the nucleotide-binding and phosphorylation domains, precluding ATP binding.

Inhibition of the type 1 inositol 1,4,5-trisphosphate-sensitive Ca2+ channel by calmodulin antagonists.

This study describes the effects of a number of calmodulin antagonists on the cerebellar type 1 inositol 1,4,5-trisphosphate (InsP3) receptor. All the antagonists tested (trifluoperazine, fluphenazine, chlorpromazine and calmidazolium) inhibited the extent of InsP3-induced Ca2+ release (IICR) with similar IC(50) values (between 60 and 85 microM). They did not affect the efficacy of InsP3 to release Ca2+, since the concentrations of InsP3 required to cause half-maximal release was little affected in the presence of these agents. In addition, these agents did not affect InsP3 binding to its receptor. Stopped-flow studies to determine the rate constants of IICR showed this process to be biphasic with a fast and slow component. All the calmodulin antagonists appeared to reduce the rate constants for Ca2+ release in a phase-specific manner, preferentially reducing the fast phase component. Chlorpromazine (75 microM) appeared to have the most potent effect on the fast phase rate constant, reducing it from 1.0 to 0.08 s(-1), while only reducing the rate constant for the slow phase about twofold (0.2-0.08 s(-1)). The fact that calmodulin itself inhibits both IICR and InsP3 binding, while these calmodulin antagonists also reduce Ca2+ release and do not affect InsP3 binding, suggests that the mechanism of action of these agents is unlikely to be due to the reversal of the modulatory action of calmodulin on this receptor.

The effects of phenothiazines and other calmodulin antagonists on the sarcoplasmic and endoplasmic reticulum Ca(2+) pumps.

The effects of a number of phenothiazines and other calmodulin antagonists on the Ca(2+)-ATPase activity of sarcoplasmic reticulum (SR) and endoplasmic reticulum (ER) were investigated. The drugs used in this study were trifluoperazine, calmidazolium, fluphenazine, chlorpromazine, W-7, and calmodulin-binding peptide. Our results showed that calmidazolium and calmodulin-binding peptide were the most potent inhibitors of skeletal muscle SR Ca(2+)-ATPase activity (isoform SERCA 1) (IC(50) values of 0.5 and 7 microM, respectively), while W-7 was the least potent inhibitor (IC(50), 125 microM). All of the antagonists had little effect on the cerebellar ER Ca(2+)-ATPase activity (isoform SERCA 2b), except for trifluoperazine, which had a biphasic effect, causing stimulation at low concentrations and inhibition at higher concentrations. Our results suggest that the effects of these calmodulin antagonists are independent of calmodulin and that they inhibit the Ca(2+)-ATPase in an isoform-specific manner. It was found that these antagonists inhibit the skeletal muscle isoform of the Ca(2+) pump by altering the Ca(2+) affinity and the associated Ca(2+)-binding steps, as well as possibly stabilising the E1 conformational state of the enzyme.

Subtype identification and functional properties of inositol 1,4, 5-trisphosphate receptors in heart and aorta.

One of the major mechanisms by which hormones elevate intracellular Ca(2+)levels is by generating the second messenger inositol 1,4, 5-trisphosphate (InsP(3)), which activates a Ca(2+)channel (InsP(3)receptor) located in the endoplasmic reticulum (ER). This study undertakes to identify the InsP(3)receptor subtypes (isoforms) in heart and aorta and to characterize their functional properties. The InsP(3)receptor isoforms were identified from rat heart and aorta tissues using both reverse-transcriptase polymerase chain reaction (RT-PCR) to assess the presence of mRNA for the different isoforms and immunochemistry using InsP(3)receptor isoform-specific antibodies. Functional studies included ligand binding experiments using [(3)H]InsP(3)and InsP(3)-induced Ca(2+)release studies using Fluo-3 as the Ca(2+)sensing dye. All three isoforms of the InsP(3)receptor were identified using RT-PCR and immunochemical analyses. [(3)H]InsP(3)binding studies using microsomes derived from these tissues showed that heart had a 3-fold lower abundance of InsP(3)receptors than aorta, while both have considerably lower abundance than the well characterized cerebellar microsomes. The affinity of the InsP(3)binding to the receptor was also different in the three tissues. In cerebellum the K(d)was 60 nM, while aorta had a much higher K(d)of 220 nM. Heart microsomes, appeared to show two classes of binding affinity with K(d)s of 150 nM and 60 nM. Furthermore, the effects of free [Ca(2+)] on [(3)H]InsP(3)binding levels were also different for the three tissues. InsP(3)binding to both cerebellar and aorta microsomes decreased by 90% and 60%, respectively, above 30 nM free [Ca(2+)], while InsP(3)binding to heart was relatively insensitive to changes in [Ca(2+)]. At maximal InsP(3)concentrations, aorta microsomes were able to release about 5% of the accumulated Ca(2+), compared to 25% by cerebellar microsomes. Heart microsomes, however, showed only very little InsP(3)-induced Ca(2+)release ( <0.5%). The EC(50)concentration for InsP(3)-induced Ca(2+)release was 1.2 micro M for aorta while that for cerebellum was 0.3 micro M. Known agonists of the cerebellar InsP(3)receptor such as 3-deoxy InsP(3)and adenophostin A were also able to mobilize Ca(2+)from aorta microsomes. In addition, the competitive antagonist heparin and the non-competitive antagonists of the cerebellar InsP(3)receptor, tetracaine and tetrahexylammonium chloride, were also able to block InsP(3)-induced Ca(2+)release from aorta microsomes.

High-performance liquid chromatographic determination of furosemide in plasma and urine and its use in bioavailability studies.

A sensitive, selective and efficient reversed-phase high-performance liquid chromatographic (HPLC) method is reported for the determination of furosemide in human plasma and urine. The method has a sensitivity limit of 5 ng/ml in plasma, with acceptable within- and between-day reproducibilities and good linearity (r2>0.99) over a concentration range from 0.05 to 2.00 microg/ml. The one-step extract of furosemide and the internal standard (warfarin) from acidified plasma or urine was eluted through a muBondapak C18 column with a mobile phase composed of 0.01 M potassium dihydrogenphosphate and acetonitrile (62:38, v/v) adjusted to pH 3.0. Within-day coefficients of variation (C.V.s) ranged from 1.08 to 8.63% for plasma and from 2.52 to 3.10% for urine, whereas between-day C.V.s ranged from 4.25 to 10.77% for plasma and from 5.15 to 6.81% for urine at three different concentrations. The minimum quantifiable concentration of furosemide was determined to be 5 ng/ml. The HPLC method described has the capability of rapid and reproducible measurement of low levels of furosemide in small amounts of plasma and urine. This method was utilized in bioavailability/pharmacokinetic studies for the routine monitoring of furosemide levels in adults, children and neonate patients.